Uses

ABSTRACT

The subject matter generally relates to methods of treatment and/or prophylaxis of CNS diseases, disorders, and/or injuries. In one aspect, the subject matter relates to inhibitors of phosphodiesterase 1 (PDE1) as neuroprotective agents and/or neural regenerative agents. In a further aspect, the subject matter relates to individuals that are at risk for the development of CNS disease or disorder.

CROSS REFERENCE TO RELATED APPLICATIONS

This Application is a U.S. continuation application of U.S. applicationSer. No. 15/406,346, filed Jan. 13, 2017, which is a U.S. continuationapplication of U.S. application Ser. No. 14/777,448, filed Sep. 15,2015, which is a U.S. National Stage application of PCT/US2014/030412,filed Mar. 17, 2014, which claims the benefit of U.S. ProvisionalApplication 61/799,603, filed on Mar. 15, 2013, the contents of each ofwhich are herein incorporated by reference in their entirety.

FIELD OF THE INVENTION

The field generally relates to methods of treatment and/or prophylaxisof CNS diseases, disorders, and/or injuries. In one aspect, the fieldrelates to inhibitors of phosphodiesterase 1 (PDE1) as neuroprotectiveagents and/or neural regenerative agents. In a further aspect, the fieldrelates to prevent the development of a CNS disease or disorder in anindividual at risk for the development of a CNS disease or disorder.

BACKGROUND OF THE INVENTION

Eleven families of phosphodiesterases (PDEs) have been identified butonly PDEs in Family I, the Ca2+-calmodulin-dependent phosphodiesterases(CaM-PDEs), which are activated by the Ca2+-calmodulin and have beenshown to mediate the calcium and cyclic nucleotide (e.g. cAMP and cGMP)signaling pathways. The three known CaM-PDE genes, PDE1A, PDE1B, andPDE1C, are all expressed in central nervous system tissue. PDE1A isexpressed throughout the brain with higher levels of expression in theCA1 to CA3 layers of the hippocampus and cerebellum and at a low levelin the striatum. PDE1A is also expressed in the lung and heart. PDE1B ispredominately expressed in the striatum, dentate gyrus, olfactory tractand cerebellum, and its expression correlates with brain regions havinghigh levels of opaminergic innervation. Although PDE1B is primarilyexpressed in the central nervous system, it may be detected in theheart. PDE1C is expressed in olfactory epithelium, cerebellar granulecells, striatum, heart, and vascular smooth muscle.

Neurogenesis is a vital process in the brains of animals and humans,whereby new nerve cells are continuously generated throughout the lifespan of the organism. The newly born cells are able to differentiateinto functional cells of the central nervous system and integrate intoexisting neural circuits in the brain. Neurogenesis is known to persistthroughout adulthood in two regions of the mammalian brain: thesubventricular zone (SVZ) of the lateral ventricles and the dentategyrus of the hippocampus. In these regions, multipotent neuralprogenitor cells (NPCs) continue to divide and give rise to newfunctional neurons and glial cells (for review Gage 2000). It has beenshown that a variety of factors can stimulate adult hippocampalneurogenesis, e.g., adrenalectomy, voluntary exercise, enrichedenvironment, hippocampus dependent learning and antidepressants (Yehuda1989, van Praag 1999, Brown J 2003, Gould 1999, Malberg 2000, Santarelli2003). Other factors, such as adrenal hormones, stress, age and drugs ofabuse negatively influence neurogenesis (Cameron 1994, McEwen 1999, Kuhn1996, Eisch 2004).

While the importance of neurogenesis cannot be overstated, the failureof axons to regenerate after spinal cord injury still remains one of thegreatest challenges facing both medicine and neuroscience. An importantdevelopment, however, has been the identification of inhibitory proteinsin CNS myelin. One problem that causes the failure of CNS neuronregeneration is inhibition of neurite outgrowth by certain bioactivemolecules. Myelin contributes to a number of proteins that have shown toinhibit neurite process outgrowth. NogoA is the first protein identifiedon the surface of the oligodendrocytes and some axons. Other proteinsthat can contribute to inhibition include myelin-associated glycoprotein(MAG), oligodendrocyte-myelin glycoprotein (OMgp) and the proteoglycanversican.

It is believed that the central nervous system (CNS) environment couldlimit axonal regeneration after injury. Indeed, CNS myelin has beenidentified as a major factor contributing to regenerative failure. Thereare those in the field that believe, and have provided evidence, thatCNS myelin contains proteins that inhibit axonal growth.

Various strategies have been proposed for overcoming myelin inhibition.One strategy that has been effective has been to elevate the levels ofintracellular cAMP. Some manners in which this may be done include: aperipheral conditioning lesion, administration of cAMP analogues,priming with neurotrophins or treatment with the phosphodiesteraseinhibitor rolipram (PDE4 inhibitor). The effects of cAMP may betranscription dependent, and cAMP-mediated activation of CREB may leadto upregulation and expression of genes such as arginase I andinterleukin-6. The products of these genes are believed to promoteaxonal regeneration, which raises the possibility that othercAMP-regulated genes could yield additional agents that would bebeneficial in the treatment of spinal cord injury. However, with regardto increasing the expression of IL-6, one significant disadvantage tothis mechanism of action may be that IL-6 is a potentially harmfulpro-inflammatory cytokine, meaning, it is possible that high levels ofIL-6 could actually exacerbate the inflammation that occurs after spinalcord injury which could then lead to increase in cell death. Indeed, afactor supporting this concern is that IL-6 transgenic mice have beenobserved to have extensive astrogliosis, neurodegeneration, andbreakdown of the blood brain barrier.

SUMMARY OF THE INVENTION

It is an advantage of the present invention that a PDE1 inhibitor (e.g.,a compound of any of Formula I-XI) may act as a neuroprotective agentand/or neuroregenerative agent. In the event of a CNS injury (e.g.,spinal cord injury), disease, or disorder, the compounds and methodsdisclosed herein may be employed to aid or enhance neurite outgrowth andaxonal regeneration even in the presence of myelin inhibitors.

Without being bound by any particular theory, it is believed to be atleast one advantage of the present invention that the administration ofa PDE1 inhibitor (e.g., any compound of Formula I-XI) may act toincrease levels of intracellular cAMP and initiate the transcription ofgenes that are necessary for overcoming myelin inhibitors and promotingneurite outgrowth and/or axonal regeneration in the case of a CNSdisease, disorder, or injury.

Furthermore, it is believed to be an advantage that the administrationof a PDE1 inhibitor (e.g., a compound of any of Formula I-XI) mayelevate the intracellular levels of both cAMP as well as cGMP. Withoutbeing bound by theory, this rise in both cAMP and cGMP may serve as acounterbalance to the potentially detrimental effects that may beassociated with chronically elevated levels of intracellular calcium. Ithas been observed that elevated levels of intracellular calcium couldhave some type of involvement in the development of various degenerativediseases. For instance, one possible explanation is that elevated levelsof intracellular calcium (e.g., chronically elevated levels ofintracellular calcium) could lead to the activation of PDE1 bycalmodulin which would have a negative effect on the expression of cAMP.

However, without being bound by any theory, it is believed that onepotential benefit of the administration of a PDE1 inhibitor (e.g., acompound of any of Formula IXI) is that this may lead to not only anincrease in cAMP, but also cGMP. This increase in intracellular cGMP maylead to an increase in the activity of PKG, preventing a further rise inintracellular calcium levels. Thus, without being bound by any theory,the administration of a PDE1 inhibitor (e.g., a compound of any ofFormula I-XI) could have the dual benefit of, for example, playing abeneficial role in axonal regeneration (and/or being neuroprotective)while simultaneously decreasing or lessening the degenerative effectsthat are possibly associated with elevated intracellular calcium levels.

In one embodiment the invention comprises compositions and methods totreat or prevent a CNS disease, disorder, or injury (e.g., spinal cordinjury, e.g., spinal muscular atrophy, e.g., motor neuron injury),wherein the method comprises administration of an effective amount of aPDE1 inhibitor (e.g., a compound of any of Formula I-XI) to modulateintracellular levels of cAMP. In one embodiment, this increase inintracellular cAMP is neuroprotective and/or aids in the increase orstimulation of neurogenesis (e.g., the PDE1 inhibitor increases neuriteoutgrowth and/or axonal regeneration).

In still a further embodiment the invention comprises compositions andmethods to treat or prevent injuries to the peripheral nervous system(PNS) wherein the method comprises administration of a PDE1 inhibitor toincrease intracellular levels of cAMP which (either directly orindirectly) increases nerve regeneration and/or is protective againstfurther nerve damage.

In one embodiment the invention comprises compositions and methods toprevent a CNS disease or disorder in a subject that is at risk fordeveloping said disease or disorder, wherein the method comprises:

1.) Obtaining a sample from the subject;

2.) Measuring the levels of intracellular calcium from the sample;

3.) Comparing the levels of intracellular calcium in the biologicalsample to a reference standard;

4.) Determining whether a patient is at risk for developing a CNSdisease or disorder based upon the level of intracellular calciumcompared to the reference standard;

5.) Administering a PDE1 inhibitor (e.g., a compound of any of FormulaI-XI) to a subject based upon the subject's levels of intracellularcalcium (e.g., administration of a PDE1 inhibitor to a subject becausethey have elevated intracellular calcium levels compared to thereference standard).

DETAILED DESCRIPTION OF THE INVENTION

Compounds for Use in the Methods of the Invention

In one embodiment, the PDE1 inhibitors for use in the methods oftreatment and prophylaxis described herein are optionally substituted4,5,7,8-tetrahydro-2H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidine or4,5,7,8,9-pentahydro-2H-pyrimido[1,2-a]pyrrolo[3,4-e]pyrimidine, e.g., aCompound of Formula II, e.g., II-A or II-B:

wherein

-   -   (i) Q is C(═O), C(═S), C(═N(R₂₀)) or CH₂;    -   (ii) L is a single bond, —N(H)—, —CH₂—, —S—, —S(O)— or —S(O₂)—;    -   (iii) R₁ is H or C₁₋₄ alkyl (e.g., methyl);    -   (iv) R₄ is H or C₁₋₆ alkyl (e.g., methyl or isopropyl) and R₂        and R₃ are, independently,        -   H        -   C₁₋₆alkyl (e.g., methyl, isopropyl) optionally substituted            with halo or hydroxy (e.g., R₂ and R₃ are both methyl, or R₂            is H and R₃ is methyl, ethyl, isopropyl or hydroxyethyl),        -   aryl,        -   heteroaryl,        -   (optionally hetero)arylalkoxy,        -   (optionally hetero)arylC₁₋₆alkyl; or        -   R₂ and R₃ together form a 3- to 6-membered ring;    -    or    -    R₂ is H and R₃ and R₄ together form a di-, tri- or        tetramethylene bridge (pref. wherein the R₃ and R₄ together have        the cis configuration, e.g., where the carbons carrying R₃ and        R₄ have the R and S configurations, respectively);    -    or    -   (v) R₅ is        -   a) -D-E-F, wherein:            -   D is C₁₋₄alkylene (e.g., methylene, ethylene or                prop-2-yn-1-ylene);            -   E is a single bond, C₂₋₄alkynylene (e.g., —C≡C—),                arylene (e.g., phenylene) or heteroarylene (e.g.,                pyridylene);            -   F is                -   H,                -   aryl (e.g., phenyl),                -   heteroaryl (e.g., pyridyl, diazolyl, triazolyl, for                    example, pyrid-2-yl, imidazol-1-yl,                    1,2,4-triazol-1-yl),                -   halo (e.g., F, Br, Cl),                -   haloC₁₋₄alkyl (e.g., trifluoromethyl),                -   —C(O)—R₁₅,                -   —N(R₁₆)(R₁₇), or                -   C₃₋₇cycloalkyl optionally containing at least one                    atom selected from a group consisting of N or O                    (e.g., cyclopentyl, cyclohexyl, pyrrolidinyl (e.g.,                    pyrrolidin-3-yl), tetrahydro-2H-pyran-4-yl, or                    morpholinyl);            -   wherein D, E and F are independently and optionally                substituted with one or more halo (e.g., F, Cl or Br),                C₁₋₄alkyl (e.g., methyl), haloC₁₋₄alkyl (e.g.,                trifluoromethyl), C₁₋₄alkoxy (e.g., methoxy), hydroxy,                C₁₋₄carboxy, or an additional aryl or heteroaryl (e.g.,                biphenyl or pyridylphenyl),            -   for example, F is heteroaryl, e.g., pyridyl substituted                with one or more halo (e.g., 6-fluoropyrid-2-yl,                5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl,                3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl,                4,6-dichloropyrid-2-yl), haloC₁₋₄alkyl (e.g.,                5-trifluoromethylpyrid-2-yl) or C₁₋₄alkyl (e.g.,                5-methylpyrid-2-yl), or F is aryl, e.g., phenyl,                substituted with one or more halo (e.g., 4-fluorophenyl)                or F is a C₃₋₇heterocycloalkyl (e.g., pyrrolidinyl)                optionally substituted with a C₁₋₆alkyl (e.g.,                1-methylpyrrolidin-3-yl); or        -   b) a substituted heteroarylalkyl, e.g., substituted with            haloC₁₋₄alkyl;        -   c) attached to the nitrogen on the pyrrolo portion of            Formula II-A or II-B and is a moiety of Formula A

-   -   -   -   wherein X, Y and Z are, independently, N or C, and R₈,                R₉, R₁₁ and R₁₂ are independently H or halogen (e.g., Cl                or F), and R₁₀ is                -   halogen,                -   C₁₋₄alkyl,                -   haloC₁₋₄alkyl (e.g., trifluoromethyl)                -   C₁₋₄alkoxy (e.g. methoxy),                -   C₃₋₇cycloalkyl,                -   heteroC₃₋₇cycloalkyl (e.g., pyrrolidinyl or                    piperidinyl),                -   C₁₋₄haloalkyl (e.g., trifluoromethyl),                -   aryl (e.g., phenyl),                -   heteroaryl (e.g., pyridyl (for example pyrid-2-yl or                    pyrid-4-yl), or thiadiazolyl (e.g.,                    1,2,3-thiadiazol-4-yl)), diazolyl (e.g.,                    imidazol-1-yl), triazolyl (e.g.,                    1,2,4-triazol-1-yl), tetrazolyl,                -   arylcarbonyl (e.g., benzoyl),                -   alkylsulfonyl (e.g., methylsulfonyl),                -   heteroarylcarbonyl, or                -   alkoxycarbonyl;            -   wherein the aryl, heteroaryl, cycloalkyl or                heterocycloalkyl is independently, optionally                substituted with one or more C₁₋₄alkyl (e.g., methyl),                halogen (e.g., chloro or fluoro), haloC₁₋₄alkyl (e.g.,                trifluoromethyl), hydroxy, C₁₋₄carboxy, —SH or an                additional aryl, heteroaryl (e.g., biphenyl or                pyridylphenyl) or C₃₋₈cycloalkyl,            -   preferably R₁₀ is phenyl, pyridyl, piperidinyl or                pyrrolidinyl optionally substituted with the                substituents previously defined, e.g. optionally                substituted with halo or alkyl            -   provided that when X, Y, or Z is nitrogen, R₈, R₉, or                R₁₀, respectively, is not present;

    -   (vi) R₆ is        -   H,        -   C₁₋₄alkyl (e.g., methyl, ethyl, n-propyl, isobutyl),        -   C₃₋₇cycloalkyl (e.g., cyclopentyl or cyclohexyl),        -   heteroC₃₋₇cycloalkyl (e.g., pyrrolidinyl, piperidinyl,            morpholinyl),        -   aryl (e.g., phenyl),        -   heteroaryl (e.g., pyrid-4-yl),        -   arylC₁₋₄alkyl (e.g., benzyl),        -   arylamino (e.g., phenylamino),        -   heteroarylamino,        -   N,N-diC₁₋₄alkylamino,        -   N,N-diarylamino,        -   N-aryl-N-(arylC₁₋₄alkyl)amino (e.g.,            N-phenyl-N-(1,1′-biphen-4-ylmethyl)amino), or        -   N(R₁₈)(R₁₉),        -   wherein the aryl and heteroaryl are optionally substituted            with one or more C₁₋₄alkyl (e.g., methyl), halogen (e.g.,            chloro or fluoro), haloC₁₋₄alkyl (e.g., trifluoromethyl),            hydroxy, C₁₋₄carboxy, or an additional aryl, heteroaryl            (e.g., biphenyl or pyridylphenyl) or C₃₋₈cycloalkyl;

    -   (vii) R₇ is H, C₁₋₆alkyl (e.g., methyl or ethyl), halogen (e.g.,        Cl), —N(R₁₈)(R₁₉), hydroxy or C₁₋₆alkoxy;

    -   (viii) n=0 or 1;

    -   (ix) when n=1, A is —C(R₁₃R₁₄)—, wherein R₁₃ and R₁₄, are,        independently, H or C₁₋₄alkyl, aryl, heteroaryl, (optionally        hetero)arylC₁₋₄alkoxy, (optionally hetero)arylC₁₋₄alkyl or R₁₄        can form a bridge with R₂ or R₄;

    -   (x) R₁₅ is C₁₋₄alkyl, haloC₁₋₄alkyl, —OH or —OC₁₋₄alkyl (e.g.,        —OCH₃)

    -   (xi) R₁₆ and R₁₇ are independently H or C₁₋₄alkyl;

    -   (xii) R₁₈ and R₁₉ are independently        -   H,        -   C₁₋₄alkyl (e.g., methyl, ethyl, n-propyl, isobutyl),        -   C₃₋₈cycloalkyl (e.g., cyclohexyl or cyclopentyl),        -   heteroC₃₋₈cycloalkyl (e.g., pyrrolidinyl, piperidinyl,            morpholinyl),        -   aryl (e.g., phenyl) or        -   heteroaryl (e.g., pyridyl),        -   wherein said aryl and heteroaryl are optionally substituted            with one or more            -   halo (e.g., fluorophenyl, e.g., 4-fluorophenyl),            -   hydroxy (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or                2-hydroxyphenyl),            -   C₁₋₄alkyl (e.g., methyl),            -   haloC₁₋₄alkyl (e.g., trifluoromethyl),            -   C₁₋₄carboxy, or            -   an additional aryl, heteroaryl (e.g., biphenyl or                pyridylphenyl) or C₃₋₈cycloalkyl,

    -   (xiii) R₂₀ is H, C₁₋₄alkyl or C₃₋₇cycloalkyl;        in free or salt form.

In another embodiment, the PDE1 inhibitors for use in the methods oftreatment and prophylaxis described herein are Compound of Formula I,e.g. Formula I-A and I-B:

wherein

-   -   (i) Q is C(═O), C(═S), C(═N(R₂₀)) or CH₂;    -   (ii) L is a single bond, —N(H)—, —CH₂—, —S—, —S(O)— or —S(O₂)—;    -   (iii) R₁ is H or C₁₋₄ alkyl (e.g., methyl);    -   (iv) R₄ is H or C₁₋₆ alkyl (e.g., methyl or isopropyl) and R₂        and R₃ are, independently,        -   H or C₁₋₆alkyl (e.g., methyl, isopropyl) optionally            substituted with halo or hydroxy (e.g., R₂ and R₃ are both            methyl, or R₂ is H and R₃ is methyl, ethyl, isopropyl or            hydroxyethyl),        -   aryl,        -   heteroaryl,        -   (optionally hetero)arylalkoxy, or        -   (optionally hetero)arylC₁₋₆alkyl;    -    or    -    R₂ is H and R₃ and R₄ together form a di-, tri- or        tetramethylene bridge (pref. wherein the R₃ and R₄ together have        the cis configuration, e.g., where the carbons carrying R₃ and        R₄ have the R and S configurations, respectively);    -   (v) R₅ is        -   a) -D-E-F, wherein:            -   D is C₁₋₄alkylene (e.g., methylene, ethylene or                prop-2-yn-1-ylene);            -   E is a single bond, C₂₋₄alkynylene (e.g., —C≡C—),                arylene (e.g., phenylene) or heteroarylene (e.g.,                pyridylene);            -   F is                -   H,                -   aryl (e.g., phenyl),                -   heteroaryl (e.g., pyridyl, diazolyl, triazolyl, for                    example, pyrid-2-yl, imidazol-1-yl,                    1,2,4-triazol-1-yl),                -   halo (e.g., F, Br, Cl),                -   haloC₁₋₄alkyl (e.g., trifluoromethyl),                -   —C(O)—R₁₅,                -   —N(R₁₆)(R₁₇), or                -   C₃₋₇cycloalkyl optionally containing at least one                    atom selected from a group consisting of N or O                    (e.g., cyclopentyl, cyclohexyl, pyrrolidinyl (e.g.,                    pyrrolidin-3-yl), tetrahydro-2H-pyran-4-yl, or                    morpholinyl);            -   wherein D, E and F are independently and optionally                substituted with one or more halo (e.g., F, Cl or Br),                C₁₋₄alkyl (e.g., methyl), haloC₁₋₄alkyl (e.g.,                trifluoromethyl), for example, F is heteroaryl, e.g.,                pyridyl substituted with one or more halo (e.g.,                6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl,                6-fluoropyrid-2-yl, 3-fluoropyrid-2-yl,                4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl),                haloC₁₋₄alkyl (e.g., 5-trifluoromethylpyrid-2-yl) or                C₁₋₄alkyl (e.g., 5-methylpyrid-2-yl), or F is aryl,                e.g., phenyl, substituted with one or more halo (e.g.,                4-fluorophenyl) or F is a C₃₋₇heterocycloalkyl (e.g.,                pyrrolidinyl) optionally substituted with a C₁₋₆alkyl                (e.g., 1-methylpyrrolidin-3-yl); or        -   b) a substituted heteroarylalkyl, e.g., substituted with            haloalkyl;        -   c) attached to the nitrogen on the pyrrolo portion of            Formula I-A or I-B and is a moiety of Formula A

-   -   -   -   wherein X, Y and Z are, independently, N or C, and R₈,                R₉, R₁₁ and R₁₂ are independently H or halogen (e.g., Cl                or F), and R₁₀ is                -   halogen,                -   C₁₋₄alkyl,                -   C₃₋₇cycloalkyl,                -   C₁₋₄haloalkyl (e.g., trifluoromethyl),                -   aryl (e.g., phenyl),                -   heteroaryl (e.g., pyridyl (for example pyrid-2-yl),                    or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)),                    diazolyl, triazolyl, tetrazolyl,                -   arylcarbonyl (e.g., benzoyl),                -   alkylsulfonyl (e.g., methylsulfonyl),                -   heteroarylcarbonyl, or                -   alkoxycarbonyl;            -   provided that when X, Y, or Z is nitrogen, R₈, R₉, or                R₁₀, respectively, is not present;

    -   (vi) R₆ is        -   H,        -   C₁₋₄alkyl,        -   C₃₋₇cycloalkyl (e.g., cyclopentyl),        -   aryl (e.g., phenyl),        -   heteroaryl (e.g., pyrid-4-yl),        -   arylC₁₋₄alkyl (e.g., benzyl),        -   arylamino (e.g., phenylamino),        -   heteroarylamino,        -   N,N-diC₁₋₄alkylamino,        -   N,N-diarylamino,        -   N-aryl-N-(arylC₁₋₄alkyl)amino (e.g.,            N-phenyl-N-(1,1′-biphen-4-ylmethyl)amino), or        -   —N(R₁₈)(R₁₉);        -   wherein the aryl or heteroaryl is optionally substituted            with one or more halo (e.g., F, Cl), hydroxy or C₁₋₆alkoxy;

    -   (vii) R₇ is H, C₁₋₆alkyl, halogen (e.g., Cl), —N(R₁₈)(R₁₉);

    -   (viii) n=0 or 1;

    -   (ix) when n=1, A is —C(R₁₃R₁₄)—, wherein R₁₃ and R₁₄, are,        independently, H or C₁₋₄alkyl, aryl, heteroaryl, (optionally        hetero)arylC₁₋₄alkoxy or (optionally hetero)arylC₁₋₄alkyl;

    -   (x) R₁₅ is C₁₋₄alkyl, haloC₁₋₄alkyl, —OH or —OC₁₋₄alkyl (e.g.,        —OCH₃)

    -   (xi) R₁₆ and R₁₇ are independently H or C₁₋₄alkyl;

    -   (xii) R₁₈ and R₁₉ are independently H, C₁₋₄alkyl or aryl (e.g.,        phenyl) wherein said aryl is optionally substituted with one or        more halo (e.g., fluorophenyl, e.g., 4-fluorophenyl) or hydroxy        (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or 2-hydroxyphenyl)

    -   (xiii) R₂₀ is H, C₁₋₄alkyl or C₃₋₇cycloalkyl;        in free or salt form.

The invention further provides optionally substituted4,5,7,8-tetrahydro-(optionally 4-thioxo or 4-imino)-(1H or2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine or 4,5,7,8,9-pentahydro-(1Hor 2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine compounds, in free orsalt form, e.g., (1 or 2 and/or 3 and/or 5)-substituted4,5,7,8-tetrahydro-1H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine,4,5,7,8-tetrahydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine,4,5,7,8-tetrahydro-(1H or2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-imine,7,8-dihydro-1H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-thione or7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-thionecompounds, e.g., a Compound of Formula III:

wherein

-   -   (xiv) Q is C(═S), C(═N(R₂₀)) or CH₂;    -   (xv) L is a single bond, —N(H)—, —CH₂—;    -   (xvi) R₁ is H or C₁₋₄ alkyl (e.g., methyl or ethyl);    -   (xvii) R₄ is H or C₁₋₆ alkyl (e.g., methyl, isopropyl) and R₂        and R₃ are, independently:        -   H or C₁₋₆alkyl (e.g., methyl or isopropyl) optionally            substituted with halo or hydroxy (e.g., R₂ and R₃ are both            methyl, or R₂ is H and R₃ is methyl, ethyl, isopropyl or            hydroxyethyl),        -   aryl,        -   heteroaryl,        -   (optionally hetero)arylalkoxy,        -   (optionally hetero)arylC₁₋₆alkyl, or        -   R₂ and R₃ together form a 3- to 6-membered ring;    -    or    -    R₂ is H and R₃ and R₄ together form a di-, tri- or        tetramethylene bridge (pref. wherein the R₃ and R₄ together have        the cis configuration, e.g., where the carbons carrying R₃ and        R₄ have the R and S configurations, respectively);    -   (xviii) R₅ is        -   d) -D-E-F, wherein:            -   D is C₁₋₄alkylene (e.g., methylene, ethylene or                prop-2-yn-1-ylene);            -   E is a single bond, C₂₋₄alkynylene (e.g., —C≡C—),                arylene (e.g., phenylene) or heteroarylene (e.g.,                pyridylene);            -   F is                -   H,                -   aryl (e.g., phenyl),                -   heteroaryl (e.g., pyridyl, diazolyl, triazolyl, for                    example, pyrid-2-yl, imidazol-1-yl,                    1,2,4-triazol-1-yl),                -   halo (e.g., F, Br, Cl),                -   haloC₁₋₄alkyl (e.g., trifluoromethyl),                -   —C(O)—R₁₅,                -   —N(R₁₆)(R₁₇),                -   —S(O)₂R₂₁ or                -   C₃₋₇cycloalkyl optionally containing at least one                    atom selected from a group consisting of N or O                    (e.g., cyclopentyl, cyclohexyl, pyrrolidinyl (e.g.,                    pyrrolidin-3-yl), tetrahydro-2H-pyran-4-yl, or                    morpholinyl);            -   wherein D, E and F are independently and optionally                substituted with one or more:                -   halo (e.g., F, Cl or Br),                -   C₁₋₄alkyl (e.g., methyl),                -   haloC₁₋₄alkyl (e.g., trifluoromethyl),                -   C₁₋₄alkoxy) or                -   C₁₋₄alkyl (e.g., 5-methylpyrid-2-yl),            -   for example, F is heteroaryl, e.g., pyridyl substituted                with one or more halo (e.g., 6-fluoropyrid-2-yl,                5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl,                3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl,                4,6-dichloropyrid-2-yl),            -   or F is aryl, e.g., phenyl, substituted with one or more                halo (e.g., 4-fluorophenyl)            -   or F is a C₃₋₇heterocycloalkyl (e.g., pyrrolidinyl)                optionally substituted with a C₁₋₆alkyl (e.g.,                1-methylpyrrolidin-3-yl);            -   or        -   e) a substituted heteroarylalkyl, e.g., substituted with            haloalkyl;        -   f) attached to one of the nitrogens on the pyrazolo portion            of Formula III and is a moiety of Formula A

-   -   -   -   wherein X, Y and Z are, independently, N or C, and R₈,                R₉, R₁₁ and R₁₂ are independently H or halogen (e.g., Cl                or F), and R₁₀ is:                -   halogen,                -   C₁₋₄alkyl,                -   C₃₋₇cycloalkyl,                -   hetC₃₋₇cycloalkyl (e.g., pyrrolidinyl or                    piperidinyl),                -   C₁₋₄haloalkyl (e.g., trifluoromethyl),                -   aryl (e.g., phenyl),                -   heteroaryl (e.g., pyridyl (for example pyrid-2-yl),                    or thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)),                    diazolyl, triazolyl, tetrazolyl,                -   arylcarbonyl (e.g., benzoyl),                -   alkylsulfonyl (e.g., methylsulfonyl),                -   heteroarylcarbonyl, or                -   alkoxycarbonyl;            -   wherein the aryl, heteroaryl, cycloalkyl or                heterocycloalkyl is independently and optionally                substituted with one or more halo (e.g., F or Cl),                C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl (e.g.,                trifluoromethyl), —SH;            -   preferably R₁₀ is phenyl, pyridyl, piperidinyl or                pyrrolidinyl optionally substituted with the                substituents previously defined, e.g. optionally                substituted with halo or alkyl            -   provided that when X, Y, or Z is nitrogen, R₈, R₉, or                R₁₀, respectively, is not present;

    -   (xix) R₆ is        -   H,        -   C₁₋₄alkyl,        -   C₃₋₇cycloalkyl (e.g., cyclopentyl),        -   aryl (e.g., phenyl),        -   heteroaryl (e.g., pyridyl, for example, pyrid-4-yl),        -   arylC₁₋₄alkyl (e.g., benzyl),        -   arylamino (e.g., phenylamino),        -   heteroarylamino,        -   N,N-diC₁₋₄alkylamino,        -   N,N-diarylamino,        -   N-aryl-N-(arylC₁₋₄alkyl)amino (e.g.,            N-phenyl-N-(1,1′-biphen-4-ylmethyl)amino), or        -   —N(R₁₈)(R₁₉);        -   wherein the aryl or heteroaryl is optionally substituted            with one or more halo (e.g., F, Cl), hydroxy, C₁₋₆alkyl,            C₁₋₆alkoxy, C₃₋₈cycloalkyl, for example, R₆ is            4-hydroxyphenyl or 4-fluorophenyl,

    -   (xx) n=0 or 1;

    -   (xxi) when n=1, A is —C(R₁₃R₁₄)—, wherein R₁₃ and R₁₄, are,        independently, H or C₁₋₄alkyl, aryl, heteroaryl, (optionally        hetero)arylC₁₋₄alkoxy, (optionally hetero)arylC₁₋₄alkyl or R₁₃        or R₁₄ can form a bridge with R₂ or R₄;

    -   (xxii) R₁₅ is C₁₋₄alkyl, haloC₁₋₄alkyl, —OH or —OC₁₋₄alkyl        (e.g., —OCH₃)

    -   (xxiii) R₁₆ and R₁₇ are independently H or C₁₋₄alkyl;

    -   (xxiv) R₁₈ and R₁₉ are independently        -   H,        -   C₁₋₄alkyl,        -   C₃₋₈cycloalkyl,        -   heteroC₃₋₈cycloalkyl,        -   aryl (e.g., phenyl), or        -   heteroaryl,        -   wherein said aryl or heteroaryl is optionally substituted            with one or more            -   halo (e.g., fluorophenyl, e.g., 4-fluorophenyl),            -   hydroxy (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or                2-hydroxyphenyl),            -   C₁₋₆alkyl,            -   haloC₁₋₆alkyl,            -   C₁₋₆alkoxy,            -   aryl,            -   heteroaryl, or            -   C₃₋₈cycloalkyl;

    -   (xxv) R₂₀ is H, C₁₋₄alkyl (e.g., methyl) or C₃₋₇cycloalkyl,

    -   (xxvi) R₂₁ is C₁₋₆alkyl;        in free or salt form.

In yet another embodiment, the invention also provides a Compound ofFormula IV:

wherein

-   -   (i) Q is C(═S), C(═N(R₂₀)) or CH₂;    -   (ii) L is a single bond, —N(H)—, —CH₂—;    -   (iii) R₁ is H or C₁₋₄ alkyl (e.g., methyl or ethyl);    -   (iv) R₄ is H or C₁₋₆ alkyl (e.g., methyl, isopropyl) and R₂ and        R₃ are, independently, H or C₁₋₆alkyl (e.g., methyl or        isopropyl) optionally substituted with halo or hydroxy (e.g., R₂        and R₃ are both methyl, or R₂ is H and R₃ is methyl, ethyl,        isopropyl or hydroxyethyl), aryl, heteroaryl, (optionally        hetero)arylalkoxy, or (optionally hetero)arylC₁₋₆alkyl;    -    or    -    R₂ is H and R₃ and R₄ together form a di-, tri- or        tetramethylene bridge (pref. wherein the R₃ and R₄ together have        the cis configuration, e.g., where the carbons carrying R₃ and        R₄ have the R and S configurations, respectively);    -   (v) R₅ is        -   a) -D-E-F, wherein:            -   D is C₁₋₄alkylene (e.g., methylene, ethylene or                prop-2-yn-1-ylene);            -   E is a single bond, C₂₋₄alkynylene (e.g., —C≡C—),                arylene (e.g., phenylene) or heteroarylene (e.g.,                pyridylene);            -   F is H, aryl (e.g., phenyl), heteroaryl (e.g., pyridyl,                diazolyl, triazolyl, for example, pyrid-2-yl,                imidazol-1-yl, 1,2,4-triazol-1-yl), halo (e.g., F, Br,                Cl), haloC₁₋₄alkyl (e.g., trifluoromethyl), —C(O)—R₁₅,                —N(R₁₆)(R₁₇), —S(O)₂R₂₁ or C₃₋₇cycloalkyl optionally                containing at least one atom selected from a group                consisting of N or O (e.g., cyclopentyl, cyclohexyl,                pyrrolidinyl (e.g., pyrrolidin-3-yl),                tetrahydro-2H-pyran-4-yl, or morpholinyl);            -   wherein D, E and F are independently and optionally                substituted with one or more:                -   halo (e.g., F, Cl or Br),                -   C₁₋₄alkyl (e.g., methyl),            -   haloC₁₋₄alkyl (e.g., trifluoromethyl),            -   for example, F is heteroaryl, e.g., pyridyl substituted                with one or more halo (e.g., 6-fluoropyrid-2-yl,                5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl,                3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl,                4,6-dichloropyrid-2-yl), haloC₁₋₄alkyl (e.g.,                5-trifluoromethylpyrid-2-yl) or C₁₋₄alkyl (e.g.,                5-methylpyrid-2-yl),            -   or F is aryl, e.g., phenyl, substituted with one or more                halo (e.g., 4-fluorophenyl)            -   or F is a C₃₋₇heterocycloalkyl (e.g., pyrrolidinyl)                optionally substituted with a C₁₋₆alkyl (e.g.,                1-methylpyrrolidin-3-yl);            -   or        -   b) a substituted heteroarylalkyl, e.g., substituted with            haloalkyl;        -   c) attached to one of the nitrogens on the pyrazolo portion            of Formula IV and is a moiety of Formula A

-   -   -   -   wherein X, Y and Z are, independently, N or C, and R₈,                R₉, R₁₁ and R₁₂ are independently H or halogen (e.g., Cl                or F), and R₁₀ is:                -   halogen,                -   C₁₋₄alkyl,                -   C₃₋₇cycloalkyl,                -   C₁₋₄haloalkyl (e.g., trifluoromethyl),                -   aryl (e.g., phenyl),                -   heteroaryl (e.g., pyridyl (for example pyrid-2-yl),                    or                -   thiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)),                    diazolyl, triazolyl, tetrazolyl,                -   arylcarbonyl (e.g., benzoyl),                -   alkylsulfonyl (e.g., methylsulfonyl),                -   heteroarylcarbonyl, or                -   alkoxycarbonyl;            -   provided that when X, Y, or Z is nitrogen, R₈, R₉, or                R₁₀, respectively, is not present;

    -   (vi) R₆ is        -   H,        -   C₁₋₄alkyl,        -   C₃₋₇cycloalkyl (e.g., cyclopentyl),        -   aryl (e.g., phenyl),        -   heteroaryl (e.g., pyridyl, for example, pyrid-4-yl),        -   arylC₁₋₄alkyl (e.g., benzyl),        -   arylamino (e.g., phenylamino),        -   heteroarylamino,        -   N,N-diC₁₋₄alkylamino,        -   N,N-diarylamino,        -   N-aryl-N-(arylC₁₋₄alkyl)amino (e.g.,            N-phenyl-N-(1,1′-biphen-4-ylmethyl)amino), or        -   —N(R₁₈)(R₁₉);        -   wherein the aryl or heteroaryl is optionally substituted            with one or more halo (e.g., F, Cl), hydroxy or C₁₋₆alkoxy,            for example, R₆ is 4-hydroxyphenyl or 4-fluorophenyl,

    -   (vii) n=0 or 1;

    -   (viii) when n=1, A is —C(R₁₃R₁₄)—, wherein R₁₃ and R₁₄, are,        independently, H or C₁₋₄alkyl, aryl, heteroaryl, (optionally        hetero)arylC₁₋₄alkoxy or (optionally hetero)arylC₁₋₄alkyl;

    -   (ix) R₁₅ is C₁₋₄alkyl, haloC₁₋₄alkyl, —OH or —OC₁₋₄alkyl (e.g.,        —OCH₃)

    -   (x) R₁₆ and R₁₇ are independently H or C₁₋₄alkyl;

    -   (xi) R₁₈ and R₁₉ are independently H, C₁₋₄alkyl or aryl (e.g.,        phenyl) wherein said aryl is optionally substituted with one or        more halo (e.g., fluorophenyl, e.g., 4-fluorophenyl) or hydroxy        (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or 2-hydroxyphenyl)

    -   (xii) R₂₀ is H, C₁₋₄alkyl (e.g., methyl) or C₃₋₇cycloalkyl,

    -   (xiii) R₂₁ is C₁₋₆alkyl;        in free or salt form.

In still yet another embodiment, the invention provides that the PDE1inhibitors for use in the methods of treatment and prophylaxis which aredescribed herein are selected from any of the Applicant's ownpublications and applications: US 2008-0188492 A1, US 2010-0173878 A1,US 2010-0273754 A1, US 2010-0273753 A1, WO 2010/065153, WO 2010/065151,WO 2010/065151, WO 2010/065149, WO 2010/065147, WO 2010/065152, WO2011/153129, WO 2011/133224, WO 2011/153135, WO 2011/153136, WO2011/153138, U.S. Ser. No. 12/064,599, U.S. Ser. No. 12/514,712, U.S.Ser. No. 12/517,945, U.S. Ser. No. 13/203,365, U.S. Ser. No. 13/319,807,U.S. Ser. No. 13/500,941 and U.S. Ser. No. 14/209,258, the entirecontents of each of which are incorporated herein by reference in theirentireties.

In yet another embodiment the invention provides that the PDE1inhibitors for use in the methods of treatment and prophylaxis describedherein are compounds of Formula V:

wherein

-   -   (i) R₁ is H or C₁₋₄ alkyl (e.g., methyl);    -   (ii) R₄ is H or C₁₋₄ alkyl and R₂ and R₃ are, independently, H        or C₁₋₄ alkyl (e.g., R₂ and R₃ are both methyl, or R₂ is H and        R₃ is isopropyl), aryl, heteroaryl, (optionally        hetero)arylalkoxy, or (optionally hetero)arylalkyl;    -   or    -   R₂ is H and R₃ and R₄ together form a di-, tri- or        tetramethylene bridge (pref. wherein the R₃ and R₄ together have        the cis configuration, e.g., where the carbons carrying R₃ and        R₄ have the R and S configurations, respectively);    -   (iii) R₅ is a substituted heteroarylalkyl, e.g., substituted        with haloalkyl    -   or    -   R₅ is attached to one of the nitrogens on the pyrazolo portion        of Formula V and is a moiety of Formula A

wherein X, Y and Z are, independently, N or C, and R₈, R₉, R₁₁ and R₁₂are independently H or halogen (e.g., Cl or F), and R₁₀ is halogen,alkyl, cycloalkyl, haloalkyl (e.g., trifluoromethyl), aryl (e.g.,phenyl), heteroaryl (e.g., pyridyl (for example pyrid-2-yl), orthiadiazolyl (e.g., 1,2,3-thiadiazol-4-yl)), diazolyl, triazolyl,tetrazolyl, arylcarbonyl (e.g., benzoyl), alkylsulfonyl (e.g.,methylsulfonyl), heteroarylcarbonyl, or alkoxycarbonyl; provided thatwhen X, Y, or Z is nitrogen, R₈, R₉, or R₁₀, respectively, is notpresent; and(iv) R₆ is H, alkyl, aryl, heteroaryl, arylalkyl (e.g., benzyl),arylamino (e.g., phenylamino), heteroarylamino, N,N-dialkylamino,N,N-diarylamino, or N-aryl-N-(arylalkyl)amino (e.g.,N-phenyl-N-(1,1′-biphen-4-ylmethyl)amino); and(v) n=0 or 1;(vi) when n=1, A is —C(R₁₃R₁₄)—

-   -   wherein R₁₃ and R₁₄, are, independently, H or C₁₋₄ alkyl, aryl,        heteroaryl, (optionally hetero)arylalkoxy or (optionally        hetero)arylalkyl;        in free, salt or prodrug form, including its enantiomers,        diastereoisomers and racemates.

In one embodiment the invention provides that the PDE1 inhibitors foruse in the methods of treatment and prophylaxis described herein arecompounds of Formula VI:

wherein:

-   -   (i) R₁ is H or alkyl;    -   (ii) R₂ is H, alkyl, cycloalkyl, haloalkyl, alkylaminoalkyl,        hydroxyalkyl, arylalkyl, heteroarylalkyl, or alkoxyarylalkyl;    -   (iii) R₃ is heteroarylmethyl or formula A

wherein X, Y and Z are, independently, N or C, and R₈, R₉, R₁₁ and R₁₂are independently H or halogen; and R₁₀ is halogen, alkyl, cycloalkyl,haloalkyl, aryl, heteroaryl, alkyl sulfonyl, arylcarbonyl,heteroarylcarbonyl, alkoxycarbonyl, or aminocarbonyl;

-   -   (iv) R₄ is aryl or heteroaryl; and    -   (v) R₅ is H, alkyl, cycloalkyl, heteroaryl, aryl, p-benzylaryl;        provided that when X, Y or X is nitrogen, R₈, R₉ or R₁₀,        respectively, is not present; wherein “alk” or “alkyl” refers to        C₁₋₆ alkyl and “cycloalkyl” refers to C₃₋₆ cycloalkyl, in free,        salt or physiologically hydrolysable and acceptable ester        prodrug form.

In one embodiment the invention provides that the PDE1 inhibitors foruse in the methods of treatment and prophylaxis described herein arecompounds of Formula VII:

(i) X is C₁₋₆alkylene (e.g., methylene, ethylene or prop-2-yn-1-ylene);

(ii) Y is a single bond, alkynylene (e.g., —C≡C—), arylene (e.g.,phenylene) or heteroarylene (e.g., pyridylene);

(iii) Z is H, aryl (e.g., phenyl), heteroaryl (e.g., pyridyl, e.g.,pyrid-2-yl), halo (e.g., F, Br, Cl), haloC₁₋₆alkyl (e.g.,trifluoromethyl), —C(O)—R¹, —N(R²)(R³), or C₃₋₇cycloalkyl optionallycontaining at least one atom selected from a group consisting of N or O(e.g., cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-4-yl, ormorpholinyl);

(iv) R¹ is C₁₋₆alkyl, haloC₁₋₆alkyl, —OH or —OC₁₋₆alkyl (e.g., —OCH₃);

(v) R² and R³ are independently H or C₁₋₆alkyl;

(vi) R⁴ and R⁵ are independently H, C₁₋₆alkyl or aryl (e.g., phenyl)optionally substituted with one or more halo (e.g., fluorophenyl, e.g.,4-fluorophenyl), hydroxy (e.g., hydroxyphenyl, e.g., 4-hydroxyphenyl or2-hydroxyphenyl) or C₁₋₆alkoxy;

(vii) wherein X, Y and Z are independently and optionally substitutedwith one or more halo (e.g., F, Cl or Br), C₁₋₆alkyl (e.g., methyl),haloC₁₋₆alkyl (e.g., trifluoromethyl), for example, Z is heteroaryl,e.g., pyridyl substituted with one or more halo (e.g.,6-fluoropyrid-2-yl, 5-fluoropyrid-2-yl, 6-fluoropyrid-2-yl,3-fluoropyrid-2-yl, 4-fluoropyrid-2-yl, 4,6-dichloropyrid-2-yl),haloC₁₋₆alkyl (e.g., 5-trifluoromethylpyrid-2-yl) or C₁₋₆-alkyl (e.g.,5-methylpyrid-2-yl), or Z is aryl, e.g., phenyl, substituted with one ormore halo (e.g., 4-fluorophenyl),

in free, salt or prodrug form.

In one embodiment the invention provides that the PDE1 inhibitors foruse in the methods of treatment and prophylaxis described herein arecompounds of Formula VIII:

wherein

-   -   (i) R₁ is H or C₁₋₆alkyl;    -   (ii) R₂ is        -   H,        -   C₁₋₆alkyl,        -   C₃₋₈cycloalkyl optionally substituted with one or more            amino,        -   C₃₋₈heterocycloalkyl optionally substituted with C₁₋₆alkyl,        -   C₃₋₈cycloalkyl-C₁₋₆alkyl,        -   C₁₋₆haloalkyl,        -   C₀₋₆alkylaminoC₀₋₆alkyl,        -   hydroxyC₁₋₆alkyl,        -   arylC₀₋₆alkyl,        -   heteroarylalkyl,        -   C₁₋₆alkoxyarylC₁₋₆alkyl, or        -   -G-J wherein:            -   G is a single bond or, alkylene;            -   J is cycloalkyl or heterocycloalkyl optionally                substituted with alkyl;    -   (iii) R₃ is        -   a) -D-E-F wherein            -   1. D is single bond, C₁₋₆alkylene or arylC₁₋₆alkylene;            -   2. E is a C₁₋₆-alkylene, arylene, C₁₋₆alkylarylene,                aminoC₁₋₆alkylene- or amino; and            -   3. F is heteroC₃₋₈cycloalkyl optionally substituted with                C₁₋₆alkyl;    -   (iv) R₄ is aryl optionally substituted with one or more halo,        hydroxyl or C₁₋₆alkoxy; heteroaryl; or heteroC₃₋₆cycloalkyl; and    -   (v) R₅ is H, C₁₋₆alkyl, C₃₋₈cycloalkyl, heteroaryl, aryl or        p-benzylaryl;        wherein “alk”, “alkyl”, “haloalkyl” or “alkoxy” refers to C₁₋₆        alkyl and “cycloalkyl” refers to C₃₋₈cycloalkyl;        in free or salt form.

In one embodiment the invention provides that the PDE1 inhibitors foruse in the methods of treatment and prophylaxis described herein arecompounds of Formula IX:

wherein

-   -   (i) Q is —C(═S)—, —C(═N(R₆))— or —C(R₁₄)(R₁₅)—;    -   (ii) R₁ is H or C₁₋₆alkyl (e.g., methyl or ethyl);    -   (iii) R₂ is        -   H,        -   C₁₋₆alkyl (e.g., isopropyl, isobutyl, 2-methylbutyl or            2,2-dimethylpropyl) wherein said alkyl group is optionally            substituted with one or more halo (e.g., fluoro) or hydroxy            (e.g., hydroxyC₁₋₆alkyl, for example 1-hydroxyprop-2-yl or            3-hydroxy-2-methylpropyl),        -   haloC₁₋₆alkyl (e.g., trifluoromethyl or            2,2,2-trifluoroethyl),        -   N(R₁₄)(R₁₅)—C₁₋₆alkyl (e.g., 2-(dimethylamino)ethyl or            2-aminopropyl),        -   arylC₀₋₆alkyl (e.g., phenyl or benzyl), wherein said aryl is            optionally substituted with one or more C₁₋₆alkoxy, for            example, C₁₋₆alkoxyarylC₀₋₆alkyl (e.g., 4-methoxybenzyl),        -   heteroarylC₀₋₆alkyl (e.g., pyridinylmethyl), wherein said            heteroaryl is optionally substituted with one or more            C₁₋₆alkoxy (e.g., C₁₋₆alkoxyheteroarylC₁₋₆alkyl);        -   -G-J wherein G is a single bond or C₁₋₆alkylene (e.g.,            methylene) and J is C₃₋₈cycloalkyl or heteroC₃₋₈cycloalkyl            (e.g., oxetan-2-yl, pyrrolidin-3-yl, pyrrolidin-2-yl)            wherein the cycloalkyl and heterocycloalkyl group are            optionally substituted with one or more C₁₋₆alkyl or amino,            for example,            -   —C₀₋₄alkyl-C₃₋₈cycloalkyl (e.g., —C₀₋₄alkyl-cyclopentyl,                —C₀₋₄alkyl-cyclohexyl or —C₀₋₄alkyl-cyclopropyl),                wherein said cycloalkyl is optionally substituted with                one or more C₁₋₆alkyl or amino (for example,                2-aminocyclopentyl or 2-aminocyclohexyl),            -   —C₀₋₄alkyl-C₃₋₈heterocycloalkyl (e.g.,                —C₀₋₄alkyl-pyrrolidinyl, for example,                —C₀₋₄alkylpyrrolidin-3-yl) wherein said heterocycloalkyl                is optionally substituted with C₁₋₆alkyl (e.g., methyl),                for example, 1-methylpyrrolidin-3-yl,                1-methyl-pyrrolindin-2-yl,                1-methyl-pyrrolindin-2-yl-methyl or                1-methyl-pyrrolindin-3-yl-methyl);    -   (iv) R₃ is        -   1) -D-E-F wherein:            -   D is a single bond, C₁₋₆alkylene (e.g., methylene), or                arylC₁₋₆alkylene (e.g., benzylene or —CH₂C₆H₄—);            -   E is                -   a single bond,                -   C₁₋₄alkylene (e.g., methylene, ethynylene,                    prop-2-yn-1-ylene),                -   C₀₋₄alkylarylene (e.g., phenylene or —C₆H₄—,                    -benzylene- or —CH₂C₆H₄—), wherein the arylene group                    is optionally substituted with halo (e.g., Cl or F),                -   heteroarylene (e.g., pyridinylene or                    pyrimidinylene),                -   aminoC₁₋₆alkylene (e.g., —CH₂N(H)—),                -   amino (e.g., —N(H)—);                -   C₃₋₈cycloalkylene optionally containing one or more                    heteroatom selected from N or O (e.g.,                    piperidinylene),            -   F is                -   H,                -   halo (e.g., F, Br, Cl),                -   C₁₋₆alkyl (e.g., isopropyl or isobutyl),                -   haloC₁₋₆alkyl (e.g., trifluoromethyl),                -   aryl (e.g., phenyl),                -   C₃₋₈cycloalkyl optionally containing one or more                    atom selected from a group consisting of N, S or O                    (e.g., cyclopentyl, cyclohexyl, piperidinyl,                    pyrrolidinyl, tetrahydro-2H-pyran-4-yl, or                    morpholinyl), and optionally substituted with one or                    more C₁₋₆alkyl (e.g., methyl or isopropyl), for                    example, 1-methylpyrrolidin-2-yl, pyrrolidin-1-yl,                    pyrrolidin-2-yl, piperidin-2-yl,                    1-methylpiperidin-2-yl, 1-ethylpiperidin-2-yl,                -   heteroaryl (e.g., pyridyl (for example, pyrid-2-yl),                    pyrimidinyl (for example, pyrimidin-2-yl),                    thiadiazolyl (for example, 1,2,3-thiadiazol-4-yl),                    diazolyl (e.g., pyrazolyl (for example,                    pyrazol-1-yl) or imidazolyl (for example,                    imidazol-1-yl, 4-methylimidazolyl,                    1-methylimidazol-2-yl)), triazolyl (e.g.,                    1,2,4-triazol-1-yl), tetrazolyl (e.g.,                    tetrazol-5-yl), alkyloxadiazolyl (e.g.,                    5-methyl-1,2,4-oxadiazol), wherein said heteroaryl                    is optionally substituted with one or more                    C₁₋₆alkyl, halo (e.g., fluoro) or haloC₁₋₆alkyl;                -   C₁₋₆alkoxy,                -   —O-haloC₁₋₆alkyl (e.g., —O—CF₃),                -   C₁₋₆alkylsulfonyl (for example, methylsulfonyl or                    —S(O)₂CH₃),                -   —C(O)—R₁₃, wherein R₁₃ is —N(R₁₄)(R₁₅), C₁₋₆alkyl                    (e.g., methyl), —OC₁₋₆alkyl (e.g., —OCH₃),                    haloC₁₋₆alkyl (trifluoromethyl), aryl (e.g.,                    phenyl), or heteroaryl;                -   —N(R₁₄)(R₁₅);            -   or        -   2) a substituted heteroarylC₁₋₆alkyl, e.g., substituted with            haloC₁₋₆alkyl;            -   or        -   3) attached to one of the nitrogens on the pyrazolo portion            of Formula I and is a moiety of Formula A

-   -   -   -   wherein:                -   X, Y and Z are, independently, N or C,                -   R₈, R₉, R₁₁ and R₁₂ are independently H or halogen                    (e.g., Cl or F); and                -   R₁₀ is                -    halogen (e.g., fluoro or chloro),                -    C₁₋₆alkyl,                -    C₃₋₈cycloalkyl,                -    heteroC₃₋₈cycloalkyl (e.g., pyrrolidinyl or                    piperidinyl),                -    haloC₁₋₆alkyl (e.g., trifluoromethyl),                -    aryl (e.g., phenyl) or heteroaryl (e.g., pyridyl,                    (for example, pyrid-2-yl) or e.g., thiadiazolyl (for                    example, 1,2,3-thiadiazol-4-yl), diazolyl, triazolyl                    (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g.,                    tetrazol-5-yl), alkyloxadiazolyl (e.g.,                    5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g.,                    pyrazol-1-yl),                -    wherein said aryl, heteroaryl, cycloalkyl or                    heterocycloalkyl is optionally substituted with one                    or more C₁₋₆alkyl (e.g., methyl), halogen (e.g.,                    chloro or fluoro), haloC₁₋₆alkyl (e.g.,                    trifluoromethyl), hydroxy, carboxy, —SH, or an                    additional aryl or heteroaryl (e.g., biphenyl or                    pyridylphenyl),                -    C₁₋₆alkyl sulfonyl (e.g., methyl sulfonyl),                -    arylcarbonyl (e.g., benzoyl),                -    heteroarylcarbonyl,                -    C₁₋₆alkoxycarbonyl, (e.g., methoxycarbonyl),                -    Aminocarbonyl,                -    —N(R₁₄)(R₁₅);                -    preferably R₁₀ is phenyl, pyridyl, piperidinyl or                    pyrrolidinyl optionally substituted with the                    substituents previously defined, e.g. optionally                    substituted with halo or alkyl;            -   provided that when X, Y or X is nitrogen, R₈, R₉ or R₁₀,                respectively, is not present;

    -   (v) R₄ and R₅ are independently:        -   H,        -   C₁₋₆alkyl (e.g., methyl, isopropyl, isobutyl, n-propyl),        -   C₃₋₈cycloalkyl (e.g., cyclopentyl or cyclohexyl),        -   C₃₋₈heterocycloalkyl (e.g., pyrrolidinyl (for example            pyrrolidin-3-yl or pyrrolidin-1-yl), piperidinyl (for            example, piperidin-1-yl), morpholinyl),        -   —C₀₋₆alkylaryl (e.g., phenyl or benzyl) or        -   —C₀₋₆alkylheteroaryl (e.g., pyrid-4-yl, pyrid-2-yl or            pyrazol-3-yl)        -   wherein said aryl or heteroaryl is optionally substituted            with one or more halo (e.g., 4-fluorophenyl), hydroxy (e.g.,            4-hydroxyphenyl), C₁₋₆alkyl, C₁₋₆alkoxy or another aryl            group (e.g., biphenyl-4-ylmethyl);

    -   (vi) R₆ is H, C₁₋₆alkyl (e.g., methyl or ethyl) or        C₃₋₈cycloalkyl;

    -   (vii) R₁₄ and R₁₅ are independently H or C₁₋₆alkyl,        in free or salt form.

In one embodiment the invention provides that the PDE1 inhibitors foruse in the methods of treatment and prophylaxis described herein areFormula X, e.g.:

Formula X-A Formula X-B wherein

-   -   (i) Q is —C(═S)—, —C(═O)—, —C(═N(R₇))— or —C(R₁₄)(R₁₅)—;    -   (ii) R₁ is H or C₁₋₆alkyl (e.g., methyl or ethyl);    -   (iii) R₂ is H, C₁₋₆alkyl (e.g., isopropyl, isobutyl,        2-methylbutyl, 2,2-dimethylpropyl) wherein said alkyl group is        optionally substituted with halo (e.g., fluoro) or hydroxy        (e.g., 1-hydroxypropan-2-yl, 3-hydroxy-2-methylpropyl), for        example, R₂ may be a trifluoromethyl or 2,2,2-trifluoroethyl,        N(R₁₄)(R₁₅)—C₁₋₆alkyl (e.g., 2-(dimethylamino)ethyl or        2-aminopropyl), arylC₁₋₆alkyl (e.g., phenyl or benzyl),        heteroarylC₁₋₆alkyl (e.g., pyridinylmethyl),        C₁₋₆alkoxyaryl-C₁₋₆alkyl (e.g., 4-methoxybenzyl); -G-J wherein:        -   G is a single bond or, alkylene (e.g., methylene); J is            cycloalkyl or heterocycloalkyl (e.g., oxetan-2-yl,            pyrolyin-3-yl, pyrolyin-2-yl) optionally substituted with            one or more C₁₋₆alkyl (e.g., (1-methylpyrolidin-2-yl)),            amino (e.g., —NH₂), for example, -G-J may be            —C₀₋₄alkyl-C₃₋₈cycloalkyl (e.g., cyclopentyl, cyclohexyl or            cyclopropylmethyl) optionally substituted with one or more            C₁₋₆alkyl, amino (e.g., —NH₂), for example,            2-aminocyclopentyl or 2-aminocyclohexyl, wherein said            cycloalkyl optionally contains one or more heteroatom            selected from N and O (e.g., pyrrolidinyl, for example,            pyrrolidin-3-yl or pyrrolidin-2-yl,            1-methyl-pyrrolindin-2-yl, 1-methyl-pyrrolindin-3-yl,            1-methyl-pyrrolindin-2-yl-methyl or            1-methyl-pyrrolindin-3-yl-methyl);    -   (iv) R₃ is        -   1) -D-E-F wherein:        -   D is a single bond, C₁₋₆alkylene (e.g., methylene), or            arylalkylene        -   (e.g., p-benzylene or —CH₂C₆H₄—);        -   E is a single bond,        -   C₁₋₆alkylene (e.g., methylene) C₂₋₆alkynylene (e.g.,            ethynylene, prop-2-yn-1-ylene), ethynylene,            prop-2-yn-1-ylene), —Co₋₄alkylarylene (e.g., phenylene or            —C₆H₄—, -benzyle{acute over (η)}ε- or —CH₂C₆H₄—), wherein            the arylene group is optionally substituted with halo (e.g.,            Cl or F), heteroarylene (e.g., pyridinylene or            pyrimidinylene), aminoCi₋₆alkylene (e.g., —CH₂N(H)—), amino            (e.g., —N(H)—);        -   C₃₋₈cycloalkylene optionally containing one or more            heteroatom selected from N or O (e.g., piperidinylene),        -   F is        -   H,        -   halo (e.g., F, Br, Cl), C₁₋₆alkyl (e.g., isopropyl or            isobutyl), haloC₁₋₆alkyl (e.g., trifluoromethyl),        -   aryl (e.g., phenyl),        -   C₃₋₈cycloalkyl optionally containing at least one atom            selected from a group consisting of N or O (e.g.,            cyclopentyl, N cyclohexyl, piperidinyl, pyrrolidinyl,            tetrahydro-2H-pyran-4-yl, or morpholinyl), said cycloalkyl            is optionally substituted with C₁₋₆alkyl (e.g., methyl or            isopropyl), for example, 1-methylpyrrolidin-2-yl,            pyrrolidin-1-yl, pyrrolidin-2-yl, piperidin-2-yl,            1-methyrpiperidin-2-yl, 1-ethylpiperidin-2-yl, heteroaryl            optionally substituted with C₁₋₆alkyl, (e.g., pyridyl, (for            example, pyrid-2-yl), pyrimidinyl (for example,            pyrimidin-2-yl), thiadiazolyl (for example,            1,2,3-thiadiazol-4-yl), diazolyl (e.g., pyrazolyl (for            example, pyrazol-1-yl) or imidazolyl (for example,            imidazol-1-yl, 4-methylimidazolyl, 1-methylimidazol-2-yl),            triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g.,            tetrazol-5-yl), alkoxadiazolyl (e.g.,            5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-1-yl),            wherein said        -   heteroaryl is optionally substituted with halo (e.g.,            fluoro) or haloCi₋₆ alkyl, for example, 6-fluoropyrid-2-yl;            amino (e.g., —NH₂), C₁₋₆alkoxy, —O-haloC₁₋₆alkyl (e.g.,            -0-CF₃), C₁₋₆alkylsulfonyl (for example, methylsulfonyl or            —S(O)₂CH₃),        -   —C(O)—R₁₃,        -   —N(R₁₄)(R₁₅); or    -   2) a substituted heteroarylalkyl, e.g., substituted with        haloalkyl; or    -   3) attached to the nitrogen on the pyrrolo portion of Formula I        and is a moiety of Formula A

-   -   wherein X, Y and Z are, independently, N or C, and R₈, R₉, R₁₁        and R₁₂ are independently H or halogen (e.g., Cl or F); and R₁₀        is halogen, C₁₋₆alkyl,    -   C₁₋₆alkoxy (e.g., methoxy), C₃₋₈cycloalkyl, heteroC₃₋₈cycloalkyl        (e.g., pyrrolidinyl) haloC₁₋₆ alkyl (e.g., trifluoromethyl),        aryl (e.g., phenyl), heteroaryl (e.g., pyridyl, (for example,        pyrid-2-yl) or e.g., thiadiazolyl (for example,        1,2,3-thiadiazol-4-yl), diazolyl (e.g., imidazolyl or        pyrazolyl), triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl        (e.g., tetrazol-5-yl), alkoxadiazolyl (e.g.,        5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g., pyrazol-1-yl),        C₁₋₆alkyl sulfonyl (e.g., methyl sulfonyl), arylcarbonyl (e.g.,        benzoyl), heteroarylcarbonyl,    -   alkoxycarbonyl, (e.g., methoxycarbonyl), aminocarbonyl; wherein        the aryl, heteroaryl, cycloalkyl or heterocycloalkyl is        optionally substituted with one or more C₁₋₆alkyl (e.g.,        methyl), halogen (e.g., chloro or fluoro), haloC₁₋₆alkyl (e.g.,        trifluoromethyl), hydroxy, carboxy, —SH, or an additional aryl        or heteroaryl (e.g., biphenyl or pyridylphenyl) preferably R₁₀        is phenyl or pyridyl, e.g., 2-pyridyl optionally substituted        with the substituents previously defined;    -   provided that when X, Y or X is nitrogen, R₈, R₉ or R₁₀,        respectively, is not present; (v) R₄ and R₅ are independently H,        Ci₋₆alkyl (e.g., methyl, isopropyl),    -   C₃₋₈cycloalkyl (e.g., cyclopentyl), C₃₋₈heterocycloalkyl (e.g.,        pyrrolidin-3-yl), aryl (e.g., phenyl) or heteroaryl (e.g.,        pyrid-4-yl, pyrid-2-yl or pyrazol-3-yl) wherein said aryl or        heteroaryl is optionally substituted with halo (e.g.,        4-fluorophenyl), hydroxy (e.g., 4-hydroxyphenyl), C₁₋₆alkyl,        C₁₋₆alkoxy or another aryl group (e.g., biphenyl-4-ylmethyl);    -   (vi) R₆ is H, C₁₋₆alkyl        (e.g., methyl), hydroxy, Ci₋₆alkoxy, aryloxy, —N(R₁₆)(R₁₇), oxo        (e.g., =0), or C₃₋₈Cycloalkyl;    -   (vii) R₇ is H, C₁₋₆alkyl (e.g., methyl) or C₃₋₈cycloalkyl        wherein said cycloalkyl is optionally substituted with one or        more oxo (e.g., 2,5-dioxopyrrolidin-1-yl);    -   (viii) R₁₃ is —N(R₁₄)(R₁₅), C₁₋₆alkyl (e.g., methyl),        —OC₁₋₆alkyl (e.g., —OCH₃), haloC₁₋₆alkyl (trifluoromethyl), aryl        (e.g., phenyl), or heteroaryl; and    -   (ix) R₁₄ and R₁₅ are independently H or C₁₋₆alkyl;    -   (x) Ri₆ and R₁₇ are independently H, C₁₋₆alkyl, aryl (e.g.,        phenyl), heteroaryl, wherein said aryl or heteroaryl is        optionally substituted with halo (e.g., fluoro), C₁₋₆alkoxy        (e.g., methoxy); in free or salt form.

In one embodiment the invention provides that the PDE1 inhibitors foruse in the methods of treatment and prophylaxis described herein areFormula XI:

wherein

-   -   (i) L is S, SO or SO₂;    -   (ii) R₂ is H or C₁₋₆alkyl (e.g., methyl or ethyl);    -   (iii) R₂ is    -   H,    -   C₁₋₆alkyl (e.g., isopropyl, isobutyl, neopentyl, 2-methylbutyl,        2,2-dimethylpropyl)    -   wherein said alkyl group is optionally substituted with halo        (e.g., fluoro) or hydroxy (e.g., 1-hydroxypropan-2-yl,        3-hydroxy-2-methylpropyl), —C₀₋₄alkyl-C₃₋₈cycloalkyl (e.g.,        cyclopentyl, cyclohexyl) optionally substituted with one or more        amino (e.g., —NH₂), for example, 2-aminocyclopentyl or        2-aminocyclohexyl), wherein said cycloalkyl optionally contains        one or more heteroatom selected from N and O and is optionally        substituted with C₁₋₆alkyl (e.g., 1-methyl-pyrrolindin-2-yl,        1-methyl-pyrrolindin-3-yl, 1-methyl-pyrrolindin-2-yl-methyl or        1-methyl-pyrrolindin-3-yl-methyl), C₃₋₈heterocycloalkyl (e.g.,        pyrrolidinyl, for example, pyrrolidin-3-yl) optionally        substituted with C₁₋₆alkyl (e.g., methyl), for example,        1-methylpyrrolidin-3-yl, C₃₋₈cycloalkyl-C₁₋₆alkyl (e.g.,        cyclopropylmethyl), haloC₁₋₆alkyl (e.g., trifluoromethyl,        2,2,2-trifluoroethyl), —N(R₁₄)(R₁₅)—C₁₋₆alkyl (e.g.,        2-(dimethylamino)ethyl,2-aminopropyl), hydroxyC₁₋₆alkyl (e.g.,        (e.g., 3-hydroxy-2-methylpropyl, 1-hydroxyprop-2-yl),        arylC₀₋₆alkyl (e.g., benzyl), heteroarylC₁₋₆alkyl (e.g.,        pyridinylmethyl), C₁₋₆alkoxyarylC₁₋₆alkyl (e.g.,        4-methoxybenzyl); -G-J wherein: G is a single bond or, alkylene        (e.g., methylene);    -   J is cycloalkyl or heterocycloalkyl (e.g., oxetan-2-yl,        pyrolyin-3-yl, pyrolyin-2-yl) optionally substituted with        C₁₋₆alkyl (e.g., (1-methylpyrrolidin-2-yl));    -   (iv) R₃ is attached to one of the nitrogens on the pyrazolo        portion of Formula I and is a moiety of Formula A

wherein X, Y and Z are, independently, N or C, and R₈, R₉,R₁₁ and R₁₂ are independently H or halogen (e.g., Cl or F); and R₁₀ ishalogen, C₁₋₆alkyl, C₃₋₈cycloalkyl, heteroC₃₋₈cycloalkyl (e.g.,pyrrolidinyl or piperidinyl) haloC₁₋₆alkyl (e.g., trifluoromethyl), aryl(e.g., phenyl), heteroaryl (e.g., pyridyl, (for example, pyrid-2-yl) ore.g., thiadiazolyl (for example, 1,2,3-thiadiazol-4-15 yl), diazolyl,triazolyl (e.g., 1,2,4-triazol-1-yl), tetrazolyl (e.g., tetrazol-5-yl),alkoxadiazolyl (e.g., 5-methyl-1,2,4-oxadiazol), pyrazolyl (e.g.,pyrazol-i-yi), alkyl sulfonyl (e.g., methyl sulfonyl),arylcarbonyl (e.g., benzoyl), or heteroarylcarbonyl, alkoxycarbonyl,(e.g., methoxycarbonyl), aminocarbonyl; preferably phenyl, pyridyl,e.g., 2-pyridyl, piperidinyl, or pyrrolidinyl; wherein the aryl,heteroaryl cycloalkyl or heterocycloalkyl is optionally substituted withone or more halo (e.g., F or Cl), C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₄haloalkyl

(e.g., trifluoromethyl), and/or —SH, provided that when X, Y or X isnitrogen, R₈, R₉ or R₁₀, respectively, is not present; (v) R₄ isH, C₁₋₆alkyl (e.g., methyl, isopropyl),C₃₋₈cycloalkyl (e.g., cyclopentyl), C₃₋₈heterocycloalkyl (e.g.,pyrrolidin-3-yl), aryl (e.g., phenyl) or heteroaryl (e.g., pyrid-4-yl,pyrid-2-yl or pyrazol-3-yl) wherein said aryl or heteroaryl isoptionally substituted with halo (e.g., 4-fluorophenyl), hydroxy (e.g.,4-hydroxyphenyl), C₁₋₆alkyl, C₁₋₆alkoxy or another aryl group (e.g.,biphenyl-4-ylmethyl); (vi) R₁₄ and R₁₅ are independently H or C₁₋₆alkyl,in free or salt form.

The invention further provides the use of PDE1 inhibitors of any of thepreceding formulae (e.g., Formula I, II, III, IV, V, VI, VII, VIII, IX,X, XI), wherein the compound is selected from any of the following:

The invention further provides the use of PDE1 inhibitors of any of thepreceding formulae (e.g., Formula I, II, III, IV, V, VI, VII, VIII, IX,X, XI), wherein the compound is selected from any of the following:

In yet another embodiment, the invention further provides the use ofPDE1 inhibitors of any of the preceding formulae (e.g., Formula I, II,III, IV, V, VI, VII, VIII, IX, X, XI), wherein the compound is selectedfrom any of the following:

In yet another embodiment, the invention further provides the use ofPDE1 inhibitors of any of the preceding formulae (e.g., Formula I, II,III, IV, V, VI, VII, VIII, IX, X, XI), wherein the compound is selectedfrom any of the following:

In a still further embodiment, the selective PDE1 inhibitors areselected from the following compounds which can be used either alone orin combination with another PDE1 inhibitor (e.g., any of Formula I-XI):

In one embodiment, selective PDE1 inhibitors of the any of the precedingformulae (e.g., Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI) arecompounds that inhibit phosphodiesterase-mediated (e.g., PDE1-mediated,especially PDE1A or PDE1C-mediated) hydrolysis of cGMP, e.g., thepreferred compounds have an IC₅₀ of less than 1 μM, preferably less than500 nM, preferably less than 50 nM, and preferably less than 5 nM in animmobilized-metal affinity particle reagent PDE assay, in free or saltform.

If not otherwise specified or clear from context, the following termsherein have the following meanings:

-   -   (a) “Alkyl” as used herein is a saturated or unsaturated        hydrocarbon moiety, preferably saturated, preferably having one        to six carbon atoms, which may be linear or branched, and may be        optionally mono-, di- or tri-substituted, e.g., with halogen        (e.g., chloro or fluoro), hydroxy, or carboxy.    -   (b) “Cycloalkyl” as used herein is a saturated or unsaturated        nonaromatic hydrocarbon moiety, preferably saturated, preferably        comprising three to nine carbon atoms, at least some of which        form a nonaromatic mono- or bicyclic, or bridged cyclic        structure, and which may be optionally substituted, e.g., with        halogen (e.g., chloro or fluoro), hydroxy, or carboxy. Wherein        the cycloalkyl optionally contains one or more atoms selected        from N and O and/or S, said cycloalkyl may also be a        heterocycloalkyl.    -   (c) “Heterocycloalkyl” is, unless otherwise indicated, saturated        or unsaturated nonaromatic hydrocarbon moiety, preferably        saturated, preferably comprising three to nine carbon atoms, at        least some of which form a nonaromatic mono- or bicyclic, or        bridged cyclic structure, wherein at least one carbon atom is        replaced with N, O or S, which heterocycloalkyl may be        optionally substituted, e.g., with halogen (e.g., chloro or        fluoro), hydroxy, or carboxy.    -   (d) “Aryl” as used herein is a mono or bicyclic aromatic        hydrocarbon, preferably phenyl, optionally substituted, e.g.,        with alkyl (e.g., methyl), halogen (e.g., chloro or fluoro),        haloalkyl (e.g., trifluoromethyl), hydroxy, carboxy, or an        additional aryl or heteroaryl (e.g., biphenyl or pyridylphenyl).    -   (e) “Heteroaryl” as used herein is an aromatic moiety wherein        one or more of the atoms making up the aromatic ring is sulfur        or nitrogen rather than carbon, e.g., pyridyl or thiadiazolyl,        which may be optionally substituted, e.g., with alkyl, halogen,        haloalkyl, hydroxy or carboxy.    -   (f) For ease of reference, the atoms on the pyrazolo-pyrimidine        core of the Compounds of the Invention are numbered in        accordance with the numbering depicted in Formula I, unless        otherwise noted.    -   (g) Wherein E is phenylene, the numbering is as follows:

-   -   (h) It is intended that wherein the substituents end in “ene”,        for example, alkylene, phenylene or arylalkylene, said        substitutents are intended to bridge or be connected to two        other substituents. Therefore, methylene is intended to be —CH₂—        and phenylene intended to be —C₆H₄— and arylalkylene is intended        to be —C₆H₄—CH₂— or —CH₂—C₆H₄—.    -   (i) The Compounds of the Invention are intended to be numbered        as follows:

Compounds of the Invention, e.g., substituted4,5,7,8-tetrahydro-2H-imidazo[1,2-a]pyrrolo[3,4-e]pyrimidine or4,5,7,8,9-pentahydro-2H-pyrimido[1,2-a]pyrrolo[3,4-e]pyrimidine, e.g.,Compounds of Formula I (Formula I-A and I-B), or a Compound of FormulaII (e.g., II-A or II-B), may exist in free or salt form, e.g., as acidaddition salts. In this specification unless otherwise indicated,language such as “Compounds of the Invention” is to be understood asembracing the compounds in any form, for example free or acid additionsalt form, or where the compounds contain acidic substituents, in baseaddition salt form. The Compounds of the Invention are intended for useas pharmaceuticals, therefore pharmaceutically acceptable salts arepreferred. Salts which are unsuitable for pharmaceutical uses may beuseful, for example, for the isolation or purification of free Compoundsof the Invention or their pharmaceutically acceptable salts, aretherefore also included.

Compounds of the Invention, encompassing any of the compounds disclosedherein, e.g., optionally substituted 4,5,7,8-tetrahydro-(optionally4-thioxo or 4-imino)-(1H or 2H)-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidineor 4,5,7,8,9-pentahydro-(1H or2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine compounds, e.g., (1 or 2and/or 3 and/or 5)-substituted4,5,7,8-tetrahydro-1H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine,4,5,7,8-tetrahydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine,4,5,7,8-tetrahydro-(1H or2H)-pyrimido[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-imine,7,8-dihydro-1H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-thione or7,8-dihydro-2H-imidazo[1,2-a]pyrazolo[4,3-e]pyrimidine-4(5H)-thionecompounds, e.g., Compounds of Formula III, or Compound of Formula IV asdescribed herein, may exist in free or salt form, e.g., as acid additionsalts.

Compounds of the Invention may in some cases also exist in prodrug form.A prodrug form is compound which converts in the body to a Compound ofthe Invention. For example when the Compounds of the Invention containhydroxy or carboxy substituents, these substituents may formphysiologically hydrolysable and acceptable esters. As used herein,“physiologically hydrolysable and acceptable ester” means esters ofCompounds of the Invention which are hydrolysable under physiologicalconditions to yield acids (in the case of Compounds of the Inventionwhich have hydroxy substituents) or alcohols (in the case of Compoundsof the Invention which have carboxy substituents) which are themselvesphysiologically tolerable at doses to be administered. Therefore,wherein the Compound of the Invention contains a hydroxy group, forexample, Compound-OH, the acyl ester prodrug of such compound, i.e.,Compound-O—C(O)—C₁₋₄alkyl, can hydrolyze in the body to formphysiologically hydrolysable alcohol (Compound-OH) on the one hand andacid on the other (e.g., HOC(O)—C₁₋₄alkyl). Alternatively, wherein theCompound of the Invention contains a carboxylic acid, for example,Compound-C(O)OH, the acid ester prodrug of such compound,Compound-C(O)O—C₁₋₄alkyl can hydrolyze to form Compound-C(O)OH andHO—C₁₋₄alkyl. As will be appreciated the term thus embraces conventionalpharmaceutical prodrug forms.

In another embodiment, the invention further provides a pharmaceuticalcomposition comprising a Compound of the Invention, in free orpharmaceutically acceptable salt form, in admixture with apharmaceutically acceptable carrier.

Compounds of the Invention may in some cases also exist in prodrug form.A prodrug form is compound which converts in the body to a Compound ofthe Invention. For example when the Compounds of the Invention containhydroxy or carboxy substituents, these substituents may formphysiologically hydrolysable and acceptable esters. As used herein,“physiologically hydrolysable and acceptable ester” means esters ofCompounds of the Invention which are hydrolysable under physiologicalconditions to yield acids (in the case of Compounds of the Inventionwhich have hydroxy substituents) or alcohols (in the case of Compoundsof the Invention which have carboxy substituents) which are themselvesphysiologically tolerable at doses to be administered. Therefore,wherein the Compound of the Invention contains a hydroxy group, forexample, Compound-OH, the acyl ester prodrug of such compound, i.e.,Compound-O—C(O)—C₁₋₄alkyl, can hydrolyze in the body to formphysiologically hydrolysable alcohol (Compound-OH) on the one hand andacid on the other (e.g., HOC(O)—C₁₋₄alkyl). Alternatively, wherein theCompound of the Invention contains a carboxylic acid, for example,Compound-C(O)OH, the acid ester prodrug of such compound,Compound-C(O)O—C₁₋₄alkyl can hydrolyze to form Compound-C(O)OH andHO—C₁₋₄alkyl. As will be appreciated the term thus embraces conventionalpharmaceutical prodrug forms.

In another embodiment, the invention further provides a pharmaceuticalcomposition comprising a Compound of the Invention, in free,pharmaceutically acceptable salt or prodrug form, in admixture with apharmaceutically acceptable carrier.

Methods of Making Compounds of the Invention

The compounds of the Invention and their pharmaceutically acceptablesalts may be made using the methods as described and exemplified hereinand by methods similar thereto and by methods known in the chemical art.Such methods include, but not limited to, those described below. If notcommercially available, starting materials for these processes may bemade by procedures, which are selected from the chemical art usingtechniques which are similar or analogous to the synthesis of knowncompounds.

Various starting materials and/or Compounds of the Invention may beprepared using methods described in US 2008-0188492 A1, US 2010-0173878A1, US 2010-0273754 A1, US 2010-0273753 A1, WO 2010/065153, WO2010/065151, WO 2010/065151, WO 2010/065149, WO 2010/065147, WO2010/065152, WO 2011/153129, WO 2011/133224, WO 2011/153135, WO2011/153136, WO 2011/153138. All references cited herein are herebyincorporated by reference in their entirety.

The Compounds of the Invention include their enantiomers,diastereoisomers and racemates, as well as their polymorphs, hydrates,solvates and complexes. Some individual compounds within the scope ofthis invention may contain double bonds. Representations of double bondsin this invention are meant to include both the E and the Z isomer ofthe double bond. In addition, some compounds within the scope of thisinvention may contain one or more asymmetric centers. This inventionincludes the use of any of the optically pure stereoisomers as well asany combination of stereoisomers.

It is also intended that the Compounds of the Invention encompass theirstable and unstable isotopes. Stable isotopes are nonradioactiveisotopes which contain one additional neutron compared to the abundantnuclides of the same species (i.e., element). It is expected that theactivity of compounds comprising such isotopes would be retained, andsuch compound would also have utility for measuring pharmacokinetics ofthe non-isotopic analogs. For example, the hydrogen atom at a certainposition on the Compounds of the Invention may be replaced withdeuterium (a stable isotope which is non-raradioactive). Examples ofknown stable isotopes include, but not limited to, deuterium, ¹³C, ¹⁵N,¹⁸O. Alternatively, unstable isotopes, which are radioactive isotopeswhich contain additional neutrons compared to the abundant nuclides ofthe same species (i.e., element), e.g., ¹²³I, ¹³¹I, ¹²⁵I, ¹¹C, ¹⁸F, mayreplace the corresponding abundant species of I, C and F. Anotherexample of useful isotope of the compound of the invention is the ¹¹Cisotope. These radio isotopes are useful for radio-imaging and/orpharmacokinetic studies of the compounds of the invention.

Melting points are uncorrected and (dec) indicates decomposition.Temperature are given in degrees Celsius (° C.); unless otherwisestated, operations are carried out at room or ambient temperature, thatis, at a temperature in the range of 18-25° C. Chromatography meansflash chromatography on silica gel; thin layer chromatography (TLC) iscarried out on silica gel plates. NMR data is in the delta values ofmajor diagnostic protons, given in parts per million (ppm) relative totetramethylsilane (TMS) as an internal standard. Conventionalabbreviations for signal shape are used. Coupling constants (J) aregiven in Hz. For mass spectra (MS), the lowest mass major ion isreported for molecules where isotope splitting results in multiple massspectral peaks Solvent mixture compositions are given as volumepercentages or volume ratios. In cases where the NMR spectra arecomplex, only diagnostic signals are reported.

Terms and Abbreviations

-   -   BuLi=n-butyllithium    -   Bu^(t)OH=tert-butyl alcohol,    -   CAN=ammonium cerium (IV) nitrate,    -   DIPEA=diisopropylethylamine,    -   DMF=N,N-dimethylformamide,    -   DMSO=dimethyl sulfoxide,    -   Et₂O=diethyl ether,    -   EtOAc=ethyl acetate,    -   equiv.=equivalent(s),    -   h=hour(s),    -   HPLC=high performance liquid chromatography,    -   LDA=lithium diisopropylamide    -   MeOH=methanol,    -   NBS=N-bromosuccinimide    -   NCS=N-chlorosuccinimide    -   NaHCO₃=sodium bicarbonate,    -   NH₄OH=ammonium hydroxide,    -   Pd₂(dba)₃=tris[dibenzylideneacetone]dipalladium(0)    -   PMB=p-methoxybenzyl,    -   POCl₃=phosphorous oxychloride,    -   SOCl₂=thionyl chloride,    -   TFA=trifluoroacetic acid,    -   TFMSA=trifluoromethanesulfonic acid    -   THF=tetrahedrofuran.        Methods of Using Compounds of the Invention

In one embodiment the invention provides Method I, wherein Method Ifurther comprises the prophylaxis and/or treatment of diseases,disorders, and injuries of the central nervous system, wherein themethod comprises the administration of an effective amount of a PDE1inhibitor (e.g., any compound of Formula I-XI) to modulate the level ofintracellular cAMP.

For example, Method I also includes:

-   1.1. Method I, wherein the administration of the PDE1 inhibitor    enhances the axonal growth or regeneration, and/or slows or reverses    the loss of such cells in a neurodegenerative condition.-   1.2. Any of preceding Method-I, et seq., wherein the CNS disease,    disorder, or injury, refers to damage that directly or indirectly    affects the normal functioning of the CNS.-   1.3. Any of preceding Method-I, et seq., wherein the CNS disease,    disorder, or injury can be a structural, physical, or mechanical    impairment and may be caused by physical impact e.g.: crushing,    compression, or stretching of nerve fibers.-   1.4. Any of preceding Method-I, et seq., wherein the CNS disease,    disorder, or injury is a spinal cord injury.-   1.5. Method of 1.4, wherein the PDE1 inhibitor slows or arrests the    progression of the spinal cord injury.-   1.6. Any of preceding Method-I, et seq., wherein the PDE1 inhibitor    slows or arrests axonal filament degradation.-   1.7. Any of preceding Method-I, et seq. wherein the CNS disease,    disorder, or injury relates to motor neuron trauma.-   1.8. Any of preceding Method-I, et seq., wherein the disease,    disorder, or injury is selected from the group consisting of:    neurological traumas and injuries, surgery related trauma and/or    injury, retinal injury and trauma, injury related to epilepsy, cord    injury, spinal cord injury, brain injury, brain surgery, trauma    related brain injury, trauma related to spinal cord injury, brain    injury related to cancer treatment, spinal cord injury related to    cancer treatment, brain injury related to infection, brain injury    related to inflammation, spinal cord injury related to infection,    spinal cord injury related to inflammation, brain injury related to    environmental toxin, and spinal cord injury related to environmental    toxin.-   1.9. Any of preceding Method-I, et seq., wherein the CNS disease,    disorder, or injury includes neuron or nerve fibers that may be    destroyed by or degraded by an illness (e.g., Parkinson's Disease),    a chemical imbalance, or a physiological malfunction such as anoxia    (e.g., stroke), aneurysm, or reperfusion.-   1.10. Any of preceding Method-I, et seq., wherein the CNS disease,    disorder, or injury is a neurodegenerative disorder.-   1.11. Method of 1.10, wherein the neurodegenerative disease,    disorder, or injury is selected from the group consisting of:    Alzheimer's disease, Multiple Sclerosis, Spinal Muscular Atrophy,    Glaucoma, Frontotemporal dementia, Dementia with Lewy bodies,    Corticobasal degeneration, Progressive supranuclear palsy, Prion    disorders, Huntington's disease, Multiple system atrophy,    Parkinson's disease, Amyotrophic lateral sclerosis, Hereditary    spastic paraparesis, Spinocerebellar atrophies, Friedreich's ataxia,    Amyloidoses, Metabolic (diabetes) related disorders, Toxin related    disorders, chronic CNS inflammation, Charcot Marie Tooth disease,    diabetic neuropathy, cancer chemotherapy (e.g., by vinca alkaloids    and doxorubicin), brain damage associated with stroke and ischemia    associated with stroke, and neurological disorders including, but    not limited to, various peripheral neuropathic and neurological    disorders related to neurodegeneration including, but not limited    to: trigeminal neuralgia, glossopharyngeal neuralgia, Bell's palsy,    myasthenia gravis, muscular dystrophy, amyotrophic lateral    sclerosis, progressive muscular atrophy, progressive bulbar    inherited muscular atrophy, herniated, ruptured or prolapsed    vertebral disk syndromes, cervical spondylosis, plexus disorders,    thoracic outlet destruction syndromes, peripheral neuropathies such    as those caused by e.g., lead, acrylamides, gamma-diketones, carbon    disulfide, dapsone, ticks, porphyria, and Gullain-Barre syndrome.-   1.12. Any of preceding Method-I, et seq., wherein the CNS disease,    disorder, or injury is a CNS lesion, a seizure (e.g.,    electroconvulsive seizure treatment; epileptic seizures), radiation,    chemotherapy and/or stroke or other ischemic injury.-   1.13. Any of preceding Method-I, et seq., wherein the administration    of the PDE1 inhibitor is used to replenish, replace, and/or    supplement neurons and/or glial cells.-   1.14. Any of preceding Method-I, et seq., wherein the PDE1 inhibitor    (e.g., a compound of any of Formula I-XI) is administered to a    subject or a patient in need thereof.-   1.15. Any of preceding Method-I, et seq., wherein the PDE1 inhibitor    (e.g., a compound of any of Formula I-XI) elevates the level or    expression of intracellular cAMP.-   1.16. Any of preceding Method-I, et seq., wherein the PDE1 inhibitor    (e.g., a compound of any of Formula I-XI) decreases the level or    expression of intracellular cAMP.-   1.17. Any of preceding Method-I, et seq., wherein the PDE1 inhibitor    (e.g., a compound of any of Formula I-XI) modulates activity of PKA    or PKG.-   1.18. Any of preceding Method-I, et seq., wherein the PDE1 inhibitor    (e.g., a compound of any of Formula I-XI) increases the activity of    PKA or PKG.-   1.19. Any of preceding Method-I, et seq., wherein the administration    of the PDE1 inhibitor (e.g., a compound of any of Formula I-XI)    increases the level of both cAMP and cGMP.-   1.20. Any of preceding Method-I, et seq., wherein the administration    of the PDE1 inhibitor (e.g., a compound of any of Formula I-XI)    elevates the level of intracellular cAMP, and wherein this increased    level intracellular cAMP has neuroprotective and/or    neuroregenerative properties.-   1.21. Any of preceding Method-I, et seq., comprising administration    of an effective amount of the PDE1 inhibitor (e.g., a compound of    any of Formula I-XI) to a patient that suffers from a disease or    disorder related to elevated (e.g., chronically elevated)    intracellular calcium levels, and wherein the PDE1 inhibitor    prevents a further rise in said calcium levels.-   1.22. Any of preceding Method-I, et seq., wherein the PDE1 inhibitor    is administered either alone or in combination with another active    agent.-   1.23. Any of preceding Method-I, et seq., wherein the disease,    disorder, or injury is related to motor neurons, and wherein the    motor neuron disease, disorder, or injury is Multiple Sclerosis.-   1.24. Any of preceding Method-II, et seq., wherein the PDE1    inhibitor is administered in combination with another active agent    in order to treat Multiple Sclerosis.-   1.25. The method of 2.11, wherein the active agent is selected from    the group consisting of: Interferon, Glatiramer acetate,    Natalizumab, Gilenya® (fingolimod), Fampyra®, immunosuppresents, and    corticoids.

In another embodiment the invention provides for Method II, whereinMethod II comprises compositions and methods of treatment or prophylaxisof a peripheral nervous system (PNS) disease, disorder, or injury,wherein the method comprises administration of an effective amount of aPDE1 inhibitor to increase intracellular levels of cAMP.

For example, Method II also includes:

-   2.1. Method II, wherein the PNS disease, disorder, or injury, refers    to damage that directly or indirectly affects the normal functioning    of the CNS.-   2.2. Any of preceding Method-II, et seq., wherein the PDE1 inhibitor    is administered to a subject or a patient in need thereof.-   2.3. Any of preceding Method-II, et seq., wherein the PDE1 inhibitor    elevates the level or expression of intracellular cAMP.-   2.4. Any of preceding Method-II, et seq., wherein the PDE1 inhibitor    (e.g., directly or indirectly) modulates activity of PKA and/or PKG.-   2.5. Any of preceding Method-II, et seq., wherein the PDE1 inhibitor    (e.g., directly or indirectly) increases the activity of PKA and/or    PKG.-   2.6. Any of preceding Method-II, et seq., wherein the administration    of the PDE1 inhibitor increases the level of cAMP and/or cGMP.-   2.7. Any of preceding Method-II, et seq., wherein the administration    of the PDE1 inhibitor elevates the level of intracellular cAMP, and    wherein this increased level intracellular cAMP levels protects    nerve fibers, regenerates nerve fibers, or promotes nerve fiber    growth (e.g., axonal regeneration).-   2.8. Any of preceding Method-II, et seq., comprising administration    of an effective amount of the PDE1 inhibitor (e.g., a compound of    any of Formula I-XI) to a patient that suffers from a disease or    disorder related to elevated (e.g., chronically elevated)    intracellular calcium levels.-   2.9. Any of preceding Method-II, et seq., wherein the PDE1 inhibitor    is administered either alone or in combination with another active    agent.-   2.10. The method of 2.9, wherein the active agent is selected from    the IGF (e.g., IGF-1) or a steroid.-   2.11. Any of preceding Method-II, et seq. wherein the PNS disease,    disorder, or injury is selected from the group consisting of:    neuropathy (e.g., peripheral neuropathy, autonomic neuropathy, and    mononeuropathy), sciatica, carpal tunnel syndrome, polyneuropathy,    diabetic neuropathy, postherpetic neuralgia, and thoracic outlet    syndrome.

In another embodiment the invention provides for Method III, whereinMethod III comprises compositions and methods to prevent a CNS diseaseor disorder in a subject that is at risk for developing said disease ordisorder, wherein the method comprises:

-   -   1.) Obtaining a sample from the subject;    -   2.) Measuring the levels of intracellular calcium from the        sample;    -   3.) Comparing the levels of intracellular calcium in the        biological sample to a reference standard;    -   4.) Determining whether a patient is at risk for developing a        CNS disease or disorder based upon the level of intracellular        calcium compared to the reference standard;    -   5.) Administering a PDE1 inhibitor (e.g., a compound of any of        Formula I-XI) to a subject based upon the subject's levels of        intracellular calcium (e.g., administration of a PDE1 inhibitor        to a subject because they have elevated intracellular calcium        levels compared to the reference standard).

For example, Method III also includes:

-   3.1. Method III, wherein the sample is a biological sample.-   3.2. Any of preceding Method-III, et seq., wherein the patient's    intracellular calcium levels are measured using a chemical    fluorescent probe.-   3.3. Any of preceding Method-III, et seq., wherein the patient's    intracellular calcium levels are elevated compared to a control    (e.g., reference standard).-   3.4. Any of preceding Method-III, et seq., wherein a PDE1 inhibitor    is administered to a patient that is shown to have elevated    intracellular calcium levels compared to a control (e.g., reference    standard).-   3.5. Any of preceding Method-III, et seq., wherein the    administration of a PDE1 inhibitor slows or prevents the development    of a CNS and/or PNS disease or disorder, wherein the CNS disease or    disorder is one that correlates to elevated (e.g., chronically    elevated) levels of intracellular calcium.-   3.6. Any of preceding Method-III, et seq., wherein the    administration of a PDE1 inhibitor decreases the likelihood that an    individual will develop a CNS and/or PNS disease or disorder,    wherein the CNS and/or PNS disease or disorder is one that    correlates with elevated (e.g., chronically elevated) levels of    intracellular calcium (e.g., any of the diseases, disorders or    injuries listed in Method I, et seq., and Method II, et seq.).-   3.7. Any of preceding Method-III, et seq., wherein the method    optionally comprises measuring the patient's intracellular levels of    cAMP or cGMP.-   3.8. Any of preceding Method-III, et seq., wherein the PDE1    inhibitor is administered either alone or in combination with    another active agent.-   3.9. Any of preceding Method-III, et seq., wherein the PDE1    inhibitor is administered because a patient has low levels of cAMP    and/or cGMP compared to a control subject.

The phrase “Compounds of the Invention” or “PDE 1 inhibitors of theInvention” encompasses any and all of the compounds disclosed herewith,e.g., a Compound of Formula I, Formula II, Formula III, Formula IV,Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X,or Formula XI, and any sub-formula (e.g., Formula II should be read asincluding both “Formula IIa and Formula IIb).

The words “treatment” and “treating” are to be understood accordingly asembracing prophylaxis and treatment or amelioration of symptoms ofdisease as well as treatment of the cause of the disease.

For methods of treatment, the word “therapeutically effective amount” asused herein refers to an amount of a drug (e.g., PDE1 inhibitor)sufficient to treat or ameliorate the pathological effects a CNS or PNSdisease, disorder, or injury. For example, a therapeutically effectiveamount of a PDE1 inhibitor may be an amount sufficient to, e.g.,increase intracellular levels of cAMP or cGMP, decrease intracellularlevels of calcium, and/or increase neuroregeneration. Where relevant, atherapeutically effective amount may also be the amount of a PDE1inhibitor necessary to slow or prevent the development of CNS or PNSdisease or disorder.

The term “patient” or “subject” refers to human or non-human (i.e.,animal) patient. In particular embodiment, the invention encompassesboth human and nonhuman. In another embodiment, the inventionencompasses nonhuman. In other embodiment, the term encompasses human.

The term “control subject” as used herein, refers to any human ornonhuman organism that does not have and/or is not suspected of having adisorder, syndrome, disease, condition and/or symptom. The term“reference standard” as used herein, refers to prior measurement andobtaining of results in a control population.

The term “biological sample” as used herein, may include any samplecomprising biological material obtained from, e.g., an organism, bodyfluid, waste product, cell or part of a cell thereof, cell line, biopsy,tissue culture or other source containing a intracellular calcium, cAMP,or cGMP levels.

A “neurogenic agent” is defined as a chemical agent or reagent that canpromote, stimulate, or otherwise increase the amount or degree or natureof neurogenesis in vivo or ex vivo or in vitro relative to the amount,degree, or nature of neurogenesis in the absence of the agent orreagent.

A “CNS injury” as used herein may include, e.g., damage to retinalganglion cells, a traumatic brain injury, a stroke-related injury, acerebral aneurism-related injury, a spinal cord injury or trauma,including monoplegia, diplegia, paraplegia, hemiplegia and quadriplegia,a neuroproliferative disorder, or neuropathic pain syndrome

A “PNS injury” as used herein may include, e.g., damage to the spinal orcranial nerves, wherein that damage may include a lesion or some acuteor chronic trauma.

Compounds of the Invention, (e.g., any of Formula I, II, III, IV, V, VI,VII, VIII, IX, X, and XI) as hereinbefore described, in free orpharmaceutically acceptable salt form, may be used as a sole therapeuticagent, but may also be used in combination or for co-administration withother active agents.

Dosages employed in practicing the present invention will of course varydepending, e.g. on the particular disease or condition to be treated,the particular Compound of the Invention used, the mode ofadministration, and the therapy desired. Compounds of the Invention maybe administered by any suitable route, including orally, parenterally,transdermally, or by inhalation, but are preferably administered orally.In general, satisfactory results, e.g. for the treatment of diseases ashereinbefore set forth are indicated to be obtained on oraladministration at dosages of the order from about 0.01 to 2.0 mg/kg. Inlarger mammals, for example humans, an indicated daily dosage for oraladministration will accordingly be in the range of from about 0.75 to150 mg, conveniently administered once, or in divided doses 2 to 4times, daily or in sustained release form. Unit dosage forms for oraladministration thus for example may comprise from about 0.2 to 75 or 150mg, e.g. from about 0.2 or 2.0 to 50, 75 or 100 mg of a Compound of theInvention, together with a pharmaceutically acceptable diluent orcarrier therefor.

Pharmaceutical compositions comprising Compounds of the Invention may beprepared using conventional diluents or excipients and techniques knownin the galenic art. Thus oral dosage forms may include tablets,capsules, solutions, suspensions and the like.

EXAMPLES Example 1

Measurement of PDEIB Inhibition In Vitro Using IMAP PhosphodiesteraseAssay Kit

Phosphodiesterase I B (PDEIB) is a calcium/calmodulin dependentphosphodiesterase enzyme that converts cyclic guanosine monophosphate(cGMP) to 5′-guanosine monophosphate (5′-GMP). PDEIB can also convert amodified cGMP substrate, such as the fluorescent moleculecGMP-fluorescein, to the corresponding GMP-fluorescein. The generationof GMP-fluorescein from cGMP-fluorescein can be quantitated, using, forexample, the IMAP (Molecular Devices, Sunnyvale, Calif.)immobilized-metal affinity particle reagent.

Briefly, the IMAP reagent binds with high affinity to the free5′-phosphate that is found in GMP-fluorescein and not incGMP-fluorescein. The resulting GMPfluorescein-IMAP complex is largerelative to cGMP-5 fluorescein. Small fluorophores that are bound up ina large, slowly tumbling, complex can be distinguished from unboundfluorophores, because the photons emitted as they fluoresce retain thesame polarity as the photons used to excite the fluorescence.

In the phosphodiesterase assay, cGMP-fluorescein, which cannot be boundto IMAP, and therefore retains little fluorescence polarization, isconverted to GMPfluorescein, which, when bound to IMAP, yields a largeincrease in fluorescence polarization (Amp). Inhibition ofphosphodiesterase, therefore, is detected as a decrease in Amp. Enzymeassay

Materials: All chemicals are available from Sigma-Aldrich (St. Louis,Mo.) except for IMAP reagents (reaction buffer, binding buffer, FL-GMPand IMAP beads), which are available from Molecular Devices (Sunnyvale,Calif.).

Assay: The following phosphodiesterase enzymes may be used:3′,5′-cyclic-nucleotide specific bovine brain phosphodiesterase (Sigma,St. Louis, Mo.) (predominantly PDEIB) and recombinant full length humanPDE1 A and PDE1B (r-hPDE1 A and r-hPDE1B respectively) which may beproduced e.g., in HEK or SF9 cells by one skilled in the art. The PDE1enzyme is reconstituted with 50% glycerol to 2.5 U/ml. One unit ofenzyme will hydrolyze 1.0 μm of 3′,5′-cAMP to 5′-AMP per min at pH 7.5at 30° C. One part enzyme is added to 1999 parts reaction buffer (30 μMCaCl 2, 10 U/ml of calmodulin (Sigma P2277), 10 mM Tris-HCl pH 7.2, 10mM MgCl2, 0.1% BSA, 0.05% NaN 3) to yield a final concentration of 1.25mU/ml. 99 μM of diluted enzyme solution is added into each well in aflat bottom 96-well polystyrene plate to which 1 μM of test compounddissolved in 100% DMSO is added. The compounds are mixed andpre-incubated with the enzyme for 10 min at room temperature.

The FL-GMP conversion reaction is initiated by combining 4 parts enzymeand inhibitor mix with 1 part substrate solution (0.225 μM) in a384-well microtiter plate. The reaction is incubated in dark at roomtemperature for 15 min. The reaction is halted by addition of 60 μM ofbinding reagent (1:400 dilution of IMAP beads in binding buffersupplemented with 1:1800 dilution of antifoam) to each well of the384-well plate. The plate is incubated at room temperature for 1 hour toallow IMAP binding to proceed to completion, and then placed in anEnvision multimode microplate reader (PerkinElmer, Shelton, Conn.) tomeasure the fluorescence polarization (Amp).

A decrease in GMP concentration, measured as decreased Amp, isindicative of inhibition of PDE activity. IC50 values are determined bymeasuring enzyme activity in the presence of 8 to 16 concentrations ofcompound ranging from 0.0037 nM to 80,000 nM and then plotting drugconcentration versus AmP, which allows IC50 values to be estimated usingnonlinear regression software (XLFit; IDBS, Cambridge, Mass.).

Example 2

A selective PDE1 inhibitor of the present invention demonstratesmicrosomal stability in human microsomal stability assays. Theaforementioned selective PDE1 inhibitor demonstrates a K value less than0.005, and demonstrates a half-life of T1/2 of about 275 minutes.

Example 3

A selective PDE1 inhibitor of the present invention demonstrates theability to cross the blood-brain barrier. Following an injection of 10mg/Kg in a suitable mouse model, the aforementioned selective PDE1inhibitor is detectable at about 3 μM less than about 0.5 hoursfollowing the injection.

The invention claimed is:
 1. A method for promoting and/or enhancingaxonal regeneration in a subject suffering from a CNS disease, disorder,and/or injury, wherein the method comprises the administration of aneffective amount of a PDE1 inhibitor to the subject, wherein theadministration of the PDE1 inhibitor modulates the subject's level ofintracellular cAMP and is sufficient for axonal regeneration, whereinthe PDE1 inhibitor is compound of Formula V:

wherein (i) R₁ is H or C1-4 alkyl; (ii) R₄ is H or C1-4 alkyl and R₂ andR₃ are, independently, H or C₁₋₄ alkyl, aryl, heteroaryl, (optionallyhetero)arylalkoxy, or (optionally hetero)arylalkyl; or R₂ is H and R₃and R₄ together form a di-, tri- or tetramethylene bridge; (iii) R₅ is asubstituted heteroarylalkyl, or R₅ is attached to one of the nitrogenson the pyrazolo portion of Formula V and is a moiety of Formula A:

wherein X, Y and Z are, independently, N or C, and R₈, R₉, R₁₁, and R₁₂are independently H or halogen, and R₁₀ is halogen, alkyl, cycloalkyl,haloalkyl, aryl, heteroaryl, diazolyl, triazolyl, tetrazolyl,arylcarbonyl, alkylsulfonyl, heteroarylcarbonyl, or alkoxycarbonyl;provided that when X, Y, or Z is nitrogen, R₈, R₉, or R₁₀ respectively,is not present; and (iv) R₆ is H, alkyl, aryl, heteroaryl, arylalkyl,arylamino, heterarylamino, N,N-dialkylamino, N,N-diarylamino, orN-aryl-N-(arylakyl)amino; and (v) n=0 or 1; (vi) when n=1, A is—C(R₁₃R₁₄)— wherein R₁₃ and R₁₄, are, independently, H or C₁₋₄ alkyl,aryl, heteroaryl, (optionally hetero)arylalkoxy or (optionallyhetero)arylalkyl; wherein aryl is optionally substituted with C₁₋₄alkyl, halogen, haloC₁₋₄alkyl, hydroxyl or C₁₋₄ carboxy or an additionalaryl or heteroaryl; or heteroaryl or thiadiazolyl is optionallysubstituted C₁₋₄alkyl, halogen, haloC₁₋₄alkyl, hydroxyl or C₁₋₄carboxy;in free or pharmaceutically acceptable salt form.
 2. The method of claim1, wherein the PDE1 inhibitor is compound of Formula VII:

(i) X is C₁₋₆alkylene; (ii) Y is a single bond, alkynylene, arylene orheteroarylene; (iii) Z is H, aryl, heteroaryl, halo, haloC₁₋₆alkyl,—C(O)—R¹, —N(R²)(R³), or C₃₋₇cycloalkyl optionally containing at leastone atom selected from a group consisting of N or O; (iv) R¹ isC₁₋₆alkyl, haloC₁₋₆alkyl, —OH or —OC₁₋₆alkyl; (v) R² and R³ areindependently H or C₁₋₆alkyl; (vi) R⁴ and R⁵ are independently H,C₁₋₆alkyl or aryl optionally substituted with one or more halo, hydroxyor C₁₋₆alkoxy; (vii) wherein X, Y and Z are independently and optionallysubstituted with one or more halo, C₁₋₆alkyl, haloC₁₋₆alkyl, in free,salt or prodrug form.
 3. The method according to claim 1, wherein theCNS disease, disorder, or injury is a spinal cord injury.
 4. The methodaccording to claim 1, wherein the CNS disease, disorder, or injuryrelates to motor neuron trauma.
 5. The method according to claim 1,wherein the CNS disease, disorder, or injury is selected from the groupconsisting of: neurological traumas and injuries, surgery related traumaand/or injury, retinal injury and trauma, injury related to epilepsy,cord injury, spinal cord injury, brain injury, brain surgery, traumarelated brain injury, trauma related to spinal cord injury, brain injuryrelated to cancer treatment, spinal cord injury related to cancertreatment, brain injury related to infection, brain injury related toinflammation, spinal cord injury related to infection, spinal cordinjury related to inflammation, brain injury related to environmentaltoxin, and spinal cord injury related to environmental toxin.
 6. Themethod according to claim 1, wherein the CNS disease, disorder, orinjury is a neurodegenerative disorder.
 7. The method according to claim6, wherein the neurodegenerative disease, disorder, or injury isselected from the group consisting of: Alzheimer's disease, MultipleSclerosis, Glaucoma, Frontotemporal dementia, Dementia with Lewy bodies,Corticobasal degeneration, Progressive supranuclear palsy, Priondisorders, Huntington's disease, Multiple system atrophy, Parkinson'sdisease, Amyotrophic lateral sclerosis, Hereditary spastic paraparesis,Spinocerebellar atrophies, Friedreich's ataxia, Amyloidoses, Metabolic(diabetes) related disorders, Toxin related disorders, chronic CNSinflammation, and Charcot Marie Tooth disease.
 8. The method of claim 1,wherein a PDE1 inhibitor is administered to a patient that is shown tohave elevated intracellular calcium levels compared to a controlsubject.
 9. The method of claim 1, wherein the PDE1 inhibitor is

in free or pharmaceutically acceptable salt form.